Pharmaceutically active compounds and methods of use

ABSTRACT

The invention provides substituted pyrazole compounds, and methods of treatment and pharmaceutical compositions that utilize or comprise one or more such compounds. Compounds of the invention are useful for the treatment of mammalian infertility.

The present application claims the benefit of U.S. provisionalapplication No. 60/205,814, filed May 19, 2000, incorporated herein byreference in its entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to substituted pyrazole compounds, andmethods of treatment and pharmaceutical compositions that utilize orcomprise one or more such compounds. Compounds of the invention areuseful for the treatment of mammalian infertility.

2. Background

Luteinizing Hormone (LH) and Follicle Stimulating Hormone (FSH) areproduced by the anterior pituitary gland and are involved in mammalianreproductive processes. The glycoprotein family of pituitary hormonessuch as FSH, LH and the thyropropic hormone (TSH) contain carbohydratemoieties and have common α-subunit and distinct β-subunits (1-4)providing receptor recognition and specificity. These proteins arerelatively large (28-38 kDa) heterodimeric glycoproteins.

LH is released from the anterior pituitary gland under the influence ofgonadotropin releasing hormone and progesterones. In the female LHstimulates ovulation and is the major hormone involved in the regulationof progesterone secretion by the corpus luteum. In the male LHstimulates Leydig cells to secrete andogens, particularly testosterone.

FSH is released from the anterior pituary under the influence ofgonadotropin releasing hormone, oestrogens and from the placenta duringpregnancy. FSH acts on the ovaries stimulating maturation of folliclesand regulates secretion of oestrogens. In the male FSH is responsiblefor the integrity of the seminiferous tubules and acts on Sertoli cellsto support gametogenesis.

The LH and FSH receptors belong to the family of G protein coupledreceptors, which are complex transmembrane proteins characterized byseven hydrophobic helices. LH and FSH receptors also share closesequence homology (approximately 40%). The receptors' extracellulardomains bind to their respective hormones with high affinity andspecificity. The intracellular portion of FSH and LH receptors iscoupled to a Gs protein. Upon receptor activation, the hormonalinteraction with the extracellular domain results in a cascade of eventsthat lead to specific biological effects of the gonadotropin.

LH and FSH have been used for treatment for female infertility andspermatogenesis disorders. See U.S. Pat. Nos. 5,767,067; 5,639,639; and5,017,557.

However, those therapies have some notable shortcomings. For instance,current FSH treatment is limited by lack of oral bioavailability, highcosts and need of close medical personnel supervision throughout anadministration protocol.

It thus would be desirable to have new agents and methods to treatinfertility in mammals.

SUMMARY OF THE INVENTION

We have now found that substituted pyrazole compounds are potentLuteinizing Hormone (LH) and Follicle Stimulating Hormone (FSH)agonists. Compounds of the invention are particularly useful fortreatment of infertility in mammals.

Pyrazole compounds of the invention are substituted by other thanhydrogen in one or more pyrazole ring positions, and preferably aresubstituted at the 1, 3, 4 and/or 5 ring positions by a non-hydrogensubstituent. Typical pyrazole compounds of the invention are substitutedat least at the 5-ring position by other than hydrogen.

Generally preferred for use in the therapeutic methods of the inventionare substituted pyrazole compounds of the following Formula I:

wherein R¹ is hydrogen; optionally substituted alkyl preferably having 1to about 20 carbons, more preferably 1 to about 12 carbons; optionallysubstituted alkenyl preferably having 2 to about 20 carbon atoms, morepreferably 2 to about 12 carbon atoms; optionally substituted alkynylpreferably having 2 to about 20 carbon atoms, more preferably 2 to about12 carbon atoms; optionally substituted carbocyclic aryl having at leastabout 6 ring carbon atoms; optionally substituted aralkyl having atleast about 6 ring carbon atoms; optionally substituted heteroaromaticor heteroalicyclic group having 1 to 3 rings, 3 to 8 ring members ineach ring and from 1 to 3 hetero atoms (N, O or S); or optionallysubstituted heteroaralkyl or heteroalicyclicalkyl group having from 1 to3 rings, 3 to 8 ring members in each ring and from 1 to 3 hetero atoms(N, O or S);

-   -   R² and R³ are each independently hydrogen, halogen, optionally        substituted alkyl preferably having 1 to about 20 carbons, more        preferably 1 to about 12 carbons; optionally substituted alkenyl        preferably having 2 to about 20 carbon atoms, more preferably 2        to about 12 carbon atoms; optionally substituted alkynyl        preferably having 2 to about 20 carbon atoms, more preferably 2        to about 12 carbon atoms; optionally substituted alkoxy        preferably having from 1 to about 20 carbon atoms, more        preferably 1 to about 12 carbon atoms; optionally substituted        alkylthio preferably having from 1 to about 20 carbon atoms,        more preferably 1 to about 12 carbon atoms; optionally        substituted alkylsulfinyl preferably having from 1 to about 20        carbon atoms, more preferably 1 to about 12 carbon atoms;        optionally substituted alkylsulfonyl preferably having from 1 to        about 20 carbon atoms, more preferably 1 to about 12 carbon        atoms; optionally substituted carbocyclic aryl having at least        about 6 ring carbon atoms; optionally substituted aralkyl having        at least about 6 ring carbon atoms; optionally substituted        heteroaromatic or heteroalicyclic group having from 1 to 3        rings, 3 to 8 ring members in each ring and from 1 to 3 hetero        atoms (particularly 1-3 N, O and/or S atoms); or optionally        substituted heteroaralkyl or heteroalicyclicalkyl group having        from 1 to 3 rings, 3 to 8 ring members in each ring and from 1        to 3 hetero atoms (particularly 1-3 N, O and/or S atoms);    -   wherein preferably at least one of R¹, R² and R³ are other than        hydrogen and more preferably at least two of R¹, R² and R³ are        other than hydrogen;    -   X is optionally substituted alkylene preferably having 1 to        about 12 chain carbons, more preferably 2 to about 8 chain        carbons, still more preferably 3 to about 6 alkylene chain        carbons; optionally substituted alkenylene preferably having 2        to about 12 chain carbons, more preferably 2 to about 8 chain        carbons, still more preferably 3 to about 6 alkenylene chain        carbons; optionally substituted alkynylene preferably having 2        to about 12 chain carbons, more preferably 2 to about 8 chain        carbons, still more preferably 3 to about 6 alkynylene chain        carbons; optionally substituted heteroalkylene preferably having        1 to about 12 chain carbons, more preferably 2 to about 8 chain        carbons, still more preferably 3 to about 6 heteroalkylene chain        carbons and a total of 4 or 5 atoms in the heteroalkylene chain        inclusive of hetero atoms (particularly N, O and/or S atoms);        optionally substituted heteroalkenylene preferably having 2 to        about 12 chain carbons, more preferably 2 to about 8 chain        carbons, still more preferably 3 to about 6 heteroalkenylene        chain carbons and a total of 4 or 5 atoms in the        heteroalkenylene chain (particularly N, O and/or S atoms);        optionally substituted heteroalkynynylene preferably having 2 to        about 12 chain carbons, more preferably 2 to about 8 chain        carbons, still more preferably 4 or 5 heteroalkynylene chain        carbons and a total of 4 or 5 atoms in the heteroalkynylene        chain inclusive of hetero atoms (particularly N, O and/or S        atoms); or X is optionally alicyclic, optionally substituted        carbocyclic aryl; optionally substituted heteroalicyclic,        optionally substituted heteroaromatic, optionally substituted        heteroaralkyl, or optionally substituted heteroalicyclicalkyl        group, each preferably having 3-10 carbon or hetero atoms in a        ring, more preferably 5 or 6 membered ring(s), and 1-3 N, O or S        atoms;    -   Y is optionally substituted amino; optionally substituted        methylene (e.g. unsubstituted methylene, CH₂), carbonyl (C═O);        or sulfonyl (SO₂);    -   Z is an optionally substituted alkylamine; an amino acid        (natural or non-natural amino acid) including a P-amino acid; or        a glycine; or a derivative thereof, attached to the rest of the        molecule either by its amino or carboxylic acid residue        depending on the nature of Y; m is 0 (where no X group is        present) or 1, and preferably m is 1; n is 0 (where no Y group        is present) or 1, and preferably n is 1; and pharmaceutically        acceptable salts thereof.

Preferred compounds of Formula I include those of the following FormulaI′:

wherein R¹, R² and R³ are each independently hydrogen; optionallysubstituted alkyl preferably having 1 to about 20 carbons, morepreferably 1 to about 12 carbons; optionally substituted alkenylpreferably having 2 to about 20 carbon atoms, more preferably 2 to about12 carbon atoms; optionally substituted alkynyl preferably having 2 toabout 20 carbon atoms, more preferably 2 to about 12 carbon atoms;optionally substituted alkoxy preferably having 1 to about 20 carbonatoms, more preferably 1 to about 12 carbon atoms; optionallysubstituted alkylthio preferably having 1 to about 20 carbon atoms, morepreferably 1 to about 12 carbon atoms; optionally substitutedalkylsulfinyl preferably having 1 to about 20 carbon atoms, morepreferably 1 to about 12 carbon atoms; optionally substitutedalkylsulfonyl preferably having 1 to about 20 carbon atoms, morepreferably 1 to about 12 carbon atoms; optionally substitutedcarbocyclic aryl having at least 6 ring carbon atoms; optionallysubstituted aralkyl having at least 6 ring atoms; optionally substitutedheteroaromatic or heteroalicyclic group having 1 to 3 rings, 3 to 8 ringmembers in each ring and from 1 to 3 hetero atoms (N, O or S); oroptionally substituted heteroaralkyl or heteroalicyclicalkyl having 1 to3 rings, 3 to 8 ring members in each ring and from 1 to 3 hetero atoms(particularly N, O or S);

-   -   X is optionally substituted alkylene preferably having 1 to        about 12 chain carbons, more preferably 2 to about 8 chain        carbons, still more preferably 3 to about 6 alkylene chain        carbons; optionally substituted alkenylene preferably having 2        to about 12 chain carbons, more preferably 2 to about 8 chain        carbons, still more preferably 3 to about 6 alkenylene chain        carbons; optionally substituted alkynylene preferably having 2        to about 12 chain carbons, more preferably 2 to about 8 chain        carbons, still more preferably 3 to about 6 alkynylene chain        carbons; optionally substituted heteroalkylene preferably having        1 to about 12 chain carbons, more preferably 1 to about 8 chain        carbons, still more preferably 3 to about 6 heteroalknylene        chain carbons and a total of 4 or 5 atoms in the heteroalkylene        chain (inclusive of N, O or S atoms); optionally substituted        heteroalkenylene preferably having 2 to about 12 chain carbons,        more preferably 2 to about 8 chain carbons, still more        preferably 3 to about 6 heteroalkenylene chain carbons and a        total of 4 or 5 atoms in the heteroalkenylene chain (inclusive        of N, O or S atoms); optionally substituted heteroalkynynylene        preferably having 2 to about 12 chain carbons, more preferably 2        to about 8 chain carbons, still more preferably 3 to about 6        heteroalkynylene chain carbons and a total of 4 or 5 atoms in        the heteroalkynylene chain (inclusive of N, O or S atoms);    -   or X is optionally substituted alicyclic; optionally substituted        carbocyclic aryl; optionally substituted aralkyl; optionally        substituted heteroaromatic; optionally substituted        heteroalicyclic group; optionally substituted heteroaralkyl; or        optionally substituted heteroalicyclicalkyl group, each        preferably having 3 to 10 carbon or hetero (N, O or S) atoms in        a ring, more preferably 5 or 6 membered ring(s), and 1-3 N, O or        S atoms;    -   Y is optionally substituted amino; optionally substituted        methylene; carbonyl; or sulfonyl;    -   Z is an optionally substituted alkylamine; an amino acid        (natural or non-natural amino acid) including a P-amino acid; or        a glycine; m is 0 (where no X group is present) or 1, and        preferably m is 1; n is 0 (where no Y group is present) or 1,        and preferably n is 1; and pharmaceutically acceptable salts        thereof.

Preferred compounds of Formula I also include those where the pyrazolering nitrogen has a non-hydrogen substituent, such as compounds of thefollowing Formula IA:

-   -   wherein R¹ is a non-hydrogen substituent selected from the same        group as defined for R¹ in Formula I above; R², R³, X, Y, Z, m        and n are the same as defined in Formula I above; and        pharmaceutically acceptable salts thereof.

Preferred R¹ groups of compounds of Formula IA include optionallysubstituted alkyl; optionally substituted alkenyl; optionallysubstituted carbocyclic aryl; optionally substituted aryalkyl;optionally substituted heteroaromatic; optionally substitutedheteroalicyclic group; optionally substituted heteroarylakyl; oroptionally substituted heteroalicyclicalkyl group.

Preferred compounds of the invention also include those having anon-hydrogen substituent at the pyrazole 1- and 3-positions, such ascompounds of the following Formula IB:

wherein R¹ and R² are each non-hydrogen substituents independentlyselected from the same group as defined for R¹ and R² in Formula Iabove; X, Y, Z, m and n are the same as defined in Formula I above; andpharmaceutically acceptable salts thereof.

Preferred R¹ groups of compounds of Formula IB include optionallysubstituted alkyl; optionally substituted alkenyl; optionallysubstituted carbocyclic aryl; optionally substituted aryalkyl;optionally substituted heteroaromatic; optionally substitutedheteroalicyclic group; optionally substituted heteroarylakyl; oroptionally substituted heteroalicyclicalkyl group.

Preferred compounds of the invention also include those having anon-hydrogen substituent at the pyrazole 1- and 3-positions, such ascompounds of the following Formula IC:

wherein R¹ and R² are each non-hydrogen substituents independentlyselected from the same group as defined in Formula I above;

-   -   R³, Y, Z, and n are the same as defined in Formula I above;    -   X is optionally substituted heteroalkylene preferably having 1        to about 12 chain carbons, more preferably 2 to about 8 chain        carbons, still more preferably 3 to about 6 heteroalkylene chain        carbons and a total of 4 or 5 atoms in the heteroalkylene chain        inclusive of N, O and/or S atoms; optionally substituted        heteroalkenylene preferably having 2 to about 12 chain carbons,        more preferably 2 to about 8 chain carbons, still more        preferably 3 to about 6 heteroalkenylene chain carbons and a        total of 4 or 5 atoms in the heteroalkenylene chain inclusive of        N, O or S atoms; optionally substituted heteroalkynynylene        preferably having 2 to about 12 chain carbons, more preferably 2        to about 8 chain carbons, still more preferably 4 or 5        heteroalkynylene chain carbons and a total of 4 or 5 atoms in        the heteroalkynylene chain inclusive of N, O or S atoms; and        pharmaceutically acceptable salts thereof.

Preferred compounds of the invention also include those having anon-hydrogen substituent at the pyrazole 1- and 3-positions, such ascompounds of the following Formula ID

wherein R¹ and R² are each non-hydrogen substituents independentlyselected from the same group as defined in Formula I above;

-   -   R³, X, Y, m and n are the same as defined in Formula I above;    -   R⁵ and R⁶ are independently hydrogen, optionally substituted        alkyl preferably having 1 to about 20 carbons, more preferably 1        to about 12 carbons; optionally substituted alkenyl preferably        having 2 to about 20 carbon atoms, more preferably 2 to about 12        carbon atoms; optionally substituted alkynyl preferably having 2        to about 20 carbon atoms, more preferably 2 to about 12 carbon        atoms; optionally substituted carbocyclic aryl having at least        about 6 ring carbon atoms; optionally substituted aralkyl having        at least about 6 ring carbon atoms; optionally substituted        heteroaromatic or heteroalicyclic group having from 1 to 3        rings, 3 to 8 ring members in each ring and from 1 to 3 hetero        atoms; or optionally substituted heteroaralkyl or        heteroalicyclicalkyl group having from 1 to 3 rings, 3 to 8 ring        members in each ring and from 1 to 3 hetero atoms more        preferably one of R⁵ and R⁶ is hydrogen; and

Q is omitted (it does not exist) or is —(CH₂)_(p)—CO-A-R⁷ wherein p is0, 1 or 2, A is O or NH and R⁷ is independently hydrogen, optionallysubstituted alkyl preferably having 1 to about 20 carbons, morepreferably 1 to about 12 carbons; optionally substituted alkenylpreferably having 2 to about 20 carbon atoms, more preferably 2 to about12 carbon atoms; optionally substituted alkynyl preferably having 2 toabout 20 carbon atoms, more preferably 2 to about 12 carbon atoms;optionally substituted carbocyclic aryl having at least about 6 ringcarbon atoms; optionally substituted aralkyl having at least about 6ring carbon atoms; optionally substituted heteroaromatic orheteroalicyclic group 1 to 3 rings, 3 to 8 ring members in each ring andfrom 1 to 3 hetero atoms (particularly 1-3 N, O and/or S atoms); oroptionally substituted heteroaralkyl or heteroalicyclicalkyl grouphaving from 1 to 3 rings, 3 to 8 ring members in each ring and from 1 to3 hetero atoms (particularly 1-3 N, O and/or S atoms); andpharmaceutically acceptable salts thereof.

Preferred compounds of the invention also include those having anon-hydrogen substituent at the pyrazole 1- and 3-positions, such ascompounds of the following Formula IE

-   -   wherein R¹ and R² are each non-hydrogen substituents        independently selected from the same group as defined in Formula        I above; R³, Y and n are the same as defined in Formula I above;        X is optionally substituted heteroalkylene preferably having 1        to about 12 chain carbons, more preferably 2 to about 8 chain        carbons, still more preferably 3 to about 6 heteroalkylene chain        carbons and a total of 4 or 5 atoms in the heteroalkylene chain        inclusive of N, O and/or S atoms; optionally substituted        heteroalkenylene preferably having 2 to about 12 chain carbons,        more preferably 2 to about 8 chain carbons, still more        preferably 3 to about 6 heteroalkenylene chain carbons and a        total of 4 or 5 atoms in the heteroalkenylene chain inclusive of        N, O and/or S atoms; optionally substituted heteroalkynynylene        preferably having 2 to about 12 chain carbons, more preferably 2        to about 8 chain carbons, still more preferably 4 or 5        heteroalkynylene chain carbons and a total of 4 or 5 atoms in        the heteroalkynylene chain inclusive of N, O and/or S atoms;    -   R⁵ and R⁶ are independently hydrogen, optionally substituted        alkyl preferably having 1 to about 20 carbons, more preferably 1        to about 12 carbons; optionally substituted alkenyl preferably        having 2 to about 20 carbon atoms, more preferably 2 to about 12        carbon atoms; optionally substituted alkynyl preferably having 2        to about 20 carbon atoms, more preferably 2 to about 12 carbon        atoms; optionally substituted carbocyclic aryl having at least        about 6 ring carbon atoms; optionally substituted aralkyl having        at least about 6 ring carbon atoms; optionally substituted        heteroaromatic or heteroalicyclic group 1 to 3 rings, 3 to 8        ring members in each ring and from 1 to 3 hetero atoms        (particularly 1-3 N, O and/or S atoms); or optionally        substituted heteroaralkyl or heteroalicyclicalkyl group having        from 1 to 3 rings, 3 to 8 ring members in each ring and from 1        to 3 hetero atom (particularly 1-3 N, O and/or S atoms), more        preferably one of R⁵ and R⁶ is hydrogen; and

Q is omitted (i.e. it is not present) or is —(CH2)_(p)—CO-A-R⁷ wherein pis 0, 1 or 2; A is O or NH and R⁷ is independently hydrogen, optionallysubstituted alkyl preferably having 1 to about 20 carbons, morepreferably 1 to about 12 carbons; optionally substituted alkenylpreferably having 2 to about 20 carbon atoms, more preferably 2 to about12 carbon atoms; optionally substituted alkynyl preferably having 2 toabout 20 carbon atoms, more preferably 2 to about 12 carbon atoms;optionally substituted carbocyclic aryl having at least about 6 ringcarbon atoms; optionally substituted aralkyl having at least about 6ring carbon atoms; optionally substituted heteroaromatic orheteroalicyclic group 1 to 3 rings, 3 to 8 ring members in each ring andfrom 1 to 3 hetero atoms (particularly 1-3 N, O and/or S atoms); oroptionally substituted heteroaralkyl or heteroalicyclicalkyl grouphaving from 1 to 3 rings, 3 to 8 ring members in each ring and from 1 to3 hetero atoms (particularly 1-3 N, O and/or S atoms); andpharmaceutically acceptable salts thereof.

Preferred compounds of the invention also include those having anon-hydrogen substituent at the pyrazole 1- and 3-positions, such ascompounds of the following Formula IF:

-   -   wherein R¹ and R² are each non-hydrogen substituents        independently selected from the same group as defined in Formula        I above;    -   R³, Y and n are the same as defined in Formula I above;    -   X is optionally alicyclic, optionally substituted carbocyclic        aryl; optionally substituted heteroalicyclic, optionally        substituted heteroaromatic, optionally substituted        heteroaralkyl, or optionally substituted heteroalicyclicalkyl        group, each preferably having 3-10 carbon or hetero atoms in a        ring, more preferably 5 or 6 membered ring(s), and 1-3 N, O or S        atoms; R⁵ and R⁶ are independently hydrogen, optionally        substituted alkyl preferably having 1 to about 20 carbons, more        preferably 1 to about 12 carbons; optionally substituted alkenyl        preferably having 2 to about 20 carbon atoms, more preferably 2        to about 12 carbon atoms; optionally substituted alkynyl        preferably having 2 to about 20 carbon atoms, more preferably 2        to about 12 carbon atoms; optionally substituted carbocyclic        aryl having at least about 6 ring carbon atoms; optionally        substituted aralkyl having at least about 6 ring carbon atoms;        optionally substituted heteroaromatic or heteroalicyclic group 1        to 3 rings, 3 to 8 ring members in each ring and from 1 to 3        hetero atoms (particularly 1-3 N, O and/or S atoms); or        optionally substituted heteroaralkyl or heteroalicyclicalkyl        group having from 1 to 3 rings, 3 to 8 ring members in each ring        and from 1 to 3 hetero atoms (particularly 1-3 N, O and/or S        atoms), more preferably one of R⁵ and R⁶ is hydrogen; and

Q is omitted (it does not exist) or is —(CH2)_(p)—CO-A-R⁷ wherein p is0, 1 or 2 A is O or NH and R⁷ is independently hydrogen, optionallysubstituted alkyl preferably having 1 to about 20 carbons, morepreferably 1 to about 12 carbons; optionally substituted alkenylpreferably having 2 to about 20 carbon atoms, more preferably 2 to about12 carbon atoms; optionally substituted alkynyl preferably having 2 toabout 20 carbon atoms, more preferably 2 to about 12 carbon atoms;optionally substituted carbocyclic aryl having at least about 6 ringcarbon atoms; optionally substituted aralkyl having at least about 6ring carbon atoms; optionally substituted heteroaromatic orheteroalicyclic group 1 to 3 rings, 3 to 8 ring members in each ring andfrom 1 to 3 hetero atoms; (particularly 1-3 N, O and/or S atoms); oroptionally substituted heteroaralkyl or heteroalicyclicalkyl grouphaving from 1 to 3 rings, 3 to 8 ring members in each ring and from 1 to3 hetero atoms (particularly 1-3 N, O and/or S atoms); andpharmaceutically acceptable salts thereof

Preferred R¹ groups of pyrazole compounds of Formulae I, I′, IA, IB, IC,ID, IE and IF are optionally substituted alkyl, optionally substitutedcarbocyclic aryl, optionally substituted aralkyl (or aryalkyl) such asoptionally substituted benzyl, and optionally substitutedheteroaromatic, particularly optionally substituted phenyl, benzyl,pyridyl and naphthyl. Generally preferred R¹ groups include C₁₋₁₆ alkyl,branched alkyl such as propyl, butyl, pentyl, and the like, particularlybranched alkyl such as i-propyl, t-butyl, sec-pentyl and the like, andoptionally substituted phenyl such as phenyl having one or more C₁₋₆alkyl substituents e.g. propyl, butyl including t-butyl, and the like.Particularly preferred R¹ groups have more significant size (molecularvolume) such as C₄₋₁₆ alkyl preferably branched such as t-butyl,isopentyl and the like, and substituted carbocyclic aryl, particularlywith branched ring substituents such phenyl substituted with t-butyl,isopentyl, trifluoromethyl, CF₃CH₂—, and the like.

Preferred R² groups of compounds of Formulae I, I′, IA, IB, IC, ID, IEand IF include optionally substituted carbocyclic aryl, particularlyoptionally substituted phenyl and naphthyl, and optionally substitutedheteroaromatic and heteroalicyclic, particularly nitrogen-containingheterocyclics such as pyridyl, tetrahydropyridyl, quinoline,isoquinoline, piperidine and the like.

Preferred X linker groups of compounds of Formulae I, I′, IA, IB and IDare alkylene groups, particularly alkylene groups having 2, 3, 4, 5, or6 chain carbon atoms (i.e. —CH₂—), more preferably 4 or 5 chain carbonatoms. Preferred X linkers groups of compounds of Formula I, I′ IA, IBand ID include carbocyclic aryl, heteroaromatic, alicyclic andheteroalicyclic groups, particularly groups having 3 to 10 ring members,more particularly 4-6 membered rings, such as optionally substitutedphenyl, thienyl, furyl, pyrrolyl and pyridyl groups. Carbonyl is apreferred Y group.

Preferred Z groups of compounds of Formulae I, I′, IA, IB, IC, ID, IEand IF comprise hydroxy moieties, particularly phenolic moieties.Substituted amines and natural and non-natural amino acids are generallypreferred Z groups. For example, preferred Z groups include optionallysubstituted C₁₋₂ alkylamine, preferably substituted with a phenolicgroup on the alkyl chain, such as —NH(CH₂)₁₋₈C₆H₄OH. Preferred Z groupsinclude tyrosine groups and other aminophenyl groups such as—NHCH(CH₂C₆H₄OH)C(═O)NH₂; —NH {CH₂C₆H₃—(N═C—NH—)}C(═O)NH₂;NH{CH₂C₆H₃—(N═N—NH—)}C(═O)NH₂ where in such groups the phenolic moietymay be substituted at any available phenyl ring position, and preferablythe hydroxyl is a meta or para substituent. Specifically preferred Zgroups including tyrosine, homo-tyrosine, 4-hydroxy-α-phenylglycine,4-amino-phenylalanine, 4-hydroxymethyl-phenylalanine,4-acetyl-amino-phenylalanine, meta-tyrosine, β-homo-tyrosine, threonine,serine, and 4-hydroxy-phenyl-ethylamine.

Also, unless otherwise indicated herein, it is understood that the aboveFormulae I, I′ IA, IB, IC, ID, IE and IF are inclusive of all possibleregio isomers of the depicted pyrazoles, even in the case of FormulaeIA, IB, IC, ID, IE and IF where the preferred regio isomer is depicted.

Particular compounds of the invention include:

-   N-{5-[1-(4-tert-butylphenyl)-3-pyridin-2-yl-1H-pyrazol-5-yl]pentanoyl}tyrosinamide;-   N-{5-[1-(4-tert-butylphenyl)-3-pyridin-3-yl-1H-pyrazol-5-yl]pentanoyl}tyrosinamide;-   N-{5-[1-(4-tert-butylphenyl)-5-pyridin-3-yl-1H-pyrazol-3-yl]pentanoyl}tyrosinamide;-   N-{5-[1-(4-tert-butylphenyl)-3-pyridin-4-yl-1H-pyrazol-5-yl]pentanoyl}tyrosinamide;-   N-{5-[1-(4-tert-butylphenyl)-5-pyridin-4-yl-1H-pyrazol-3-yl]pentanoyl}tyrosinamide;-   N-{5-[1-(4-tert-butylphenyl)-3-pyridin-3-yl-1H-pyrazol-5-yl]pentanoyl}-N,N-dimethyltyrosinamide;-   N-(3-[1-(4-tert-butylphenyl)-5-pyridin-3-yl-1H-pyrazol-3-yl]propanoyl)tyrosinamide;-   N-(3-[1-(4-tert-butylphenyl)-3-pyridin-3-yl-1H-pyrazol-5-yl]propanoyl)tyrosinamide-   N-[4-(1-butyl-3-isoquinolin-3-yl-1H-pyrazol-5-yl)benzoyl]tyrosinamide;-   N-{5-[1-(4-isopropylphenyl)-3-pyridin-3-yl-1H-pyrazol-5-yl]pentanoyl}tyrosinamide;-   N-{6-[1-(4-isopropylphenyl)-3-pyridin-2-yl-1H-pyrazol-5-yl]hexanoyl}tyrosinamide-   N-{6-[1-(4-tert-butylphenyl)-3-pyridin-2-yl-1H-pyrazol-5-yl]hexanoyl}-3-hydroxyphenylalaninamide;-   N-[1-(aminocarbonyl)-3-(4-hydroxyphenyl)propyl]-5-[1-(4-tert-butylphenyl)-3-pyridin-2-yl-1H-pyrazol-5-yl]pentanamide;-   N-[5-(1-butyl-3-isoquinolin-3-yl-1H-pyrazol-5-yl)pentanoyl]tyrosinamide;-   N-{6-[1-(4-tert-butylphenyl)-3-pyridin-2-yl-1H-pyrazol-5-yl]hexanoyl}serinamide;-   N-{6-[1-(4-iso-propylphenyl)-3-pyridin-2-yl-1H-pyrazol-5-yl]hexanoyl}serinamide;-   N-{6-[1-(4-iso-propylphenyl)-3-pyridin-2-yl-1H-pyrazol-5-yl]hexanoyl}threonamide;-   N-{5-[1-(4-isopropylphenyl)-3-pyridin-2-yl-1H-pyrazol-5-yl]pentanoyl}tyrosinamide;-   6-[1-(4-tert-butylphenyl)-3-pyridin-2-yl-1H-pyrazol-5-yl]-N-[2-(4-hydroxyphenyl)ethyl]hexanamide;-   N-{6-[1-(4-tert-butylphenyl)-3-pyridin-2-yl-1H-pyrazol-5-yl]hexanoyl}tyrosinamide;-   N-{5-[1-(4-tert-butylphenyl)-3-isoquinolin-3-yl-1H-pyrazol-5-yl]pentanoyl}tyrosinamide;-   N-{6-[1-(4-tert-butylphenyl)-3-isoquinolin-3-yl-1H-pyrazol-5-yl]hexanoyl}tyrosinamide;-   N-{6-[1-(4-tert-butylphenyl)-3-pyridin-2-yl-1H-pyrazol-5-yl]hexanoyl}-N-methyltyrosinamide;-   N-{6-[1-(4-tert-butylphenyl)-3-pyridin-2-yl-1H-pyrazol-5-yl]hexanoyl}-4-(hydroxymethyl)phenylalaninamide;    4-amino-N-{6-[1-(4-tert-butylphenyl)-3-pyridin-2-yl-1H-pyrazol-5-yl]hexanoyl}phenylalaninamide;-   4-(acetylamino)-N-{6-[1-(4-tert-butylphenyl)-3-pyridin-2-yl-1H-pyrazol-5-yl]hexanoyl}phenylalaninamide;-   4-(aminocarbonyl)-N-{6-[1-(4-tert-butylphenyl)-3-pyridin-2-yl-1H-pyrazol-5-yl]hexanoyl}phenylalaninamide;-   N-butyl-N-{6-[1-(4-tert-butylphenyl)-3-pyridin-2-yl-1H-pyrazol-5-yl]hexanoyl}tyrosinamide;-   N-{6-[1-(4-tert-butylphenyl)-3-pyridin-2-yl-1H-pyrazol-5-yl]hexanoyl}threonamide;-   N-[2-amino-1-(4-hydroxyphenyl)-2-oxoethyl]-6-[1-(4-tert-butylphenyl)-3-pyridin-2-yl-1H-pyrazol-5-yl]hexanamide;-   N-{2-[4-(aminosulfonyl)phenyl]ethyl}-5-[1-(4-tert-butylphenyl)-3-pyridin-2-yl-1H-pyrazol-5-yl]pentanamide;-   N-({5-[1-(4-isopropylphenyl)-3-pyridin-2-yl-1H-pyrazol-5-yl]thien-2-yl}carbonyl)tyrosinamide;-   N-[2-amino-1-(4-hydroxyphenyl)-2-oxoethyl]-4-[1-(4-tert-butylphenyl)-3-pyridin-2-yl-1H-pyrazol-5-yl]benzamide;-   4-[1-(4-tert-butylphenyl)-3-pyridin-2-yl-1H-pyrazol-5-yl]-N-[2-(4-hydroxyphenyl)ethyl]benzamide;-   N-{3-[1-(4-tert-butylbenzyl)-3-isoquinolin-3-yl-1H-pyrazol-5-yl]benzoyl}tyrosinamide;-   N-{5-[1-(4-tert-butylphenyl)-3-pyridin-4-yl-1H-pyrazol-5-yl]pentanoyl}tyrosinamide;-   N-{3-[1-(4-tert-butylbenzyl)-3-pyridin-3-yl-1H-pyrazol-5-yl]benzoyl}tyrosinamide;-   N-{3-[1-(4-tert-butylphenyl)-3-isoquinolin-3-yl-1H-pyrazol-5-yl]benzoyl}tyrosinamide;-   N-[4-(1-butyl-3-isoquinolin-3-yl-1H-pyrazol-5-yl)benzoyl]tyrosinamide;-   N-{3-[1-(4-tert-butylbenzyl)-3-quinolin-3-yl-1H-pyrazol-5-yl]benzoyl}tyrosinamide;-   N-{3-[3-isoquinolin-3-yl-1-(4-propylphenyl)-1H-pyrazol-5-yl]benzoyl}tyrosinamide;-   N-{5-[1-(4-tert-butylphenyl)-3-pyridin-3-yl-1H-pyrazol-5-yl]pentanoyl}tyrosinamide;-   N-{3-[1-(4-tert-butylphenyl)-3-pyridin-3-yl-1H-pyrazol-5-yl]benzoyl}tyrosinamide;-   N-{4-[1-(4-tert-butylphenyl)-3-pyridin-3-yl-1H-pyrazol-5-yl]benzoyl}tyrosinamide;-   N-{5-[1-(4-tert-butylbenzyl)-3-pyridin-4-yl-1H-pyrazol-5-yl]pentanoyl}tyrosinamide;-   N-{3-[1-(4-tert-butylbenzyl)-3-pyridin-4-yl-1H-pyrazol-5-yl]benzoyl}tyrosinamide;-   N-{5-[1-(4-tert-butylbenzyl)-3-pyridin-3-yl-1H-pyrazol-5-yl]pentanoyl}tyrosinamide;-   N-{5-[1-(4-tert-butylphenyl)-3-pyridin-4-yl-1H-pyrazol-5-yl]pentanoyl}tyrosinamide;-   N-[3-(1-butyl-3-isoquinolin-3-yl-1H-pyrazol-5-yl)benzoyl]tyrosinamide;-   N-(4-{[1-(4-tert-butylphenyl)-3-pyridin-4-yl-1H-pyrazol-5-yl]amino}butanoyl)tyrosinamide;-   N-[(1-butyl-3-pyridin-3-yl-1H-pyrazol-5-yl)methyllglycyltyrosinamide;-   N-{[1-(4-tert-butylphenyl)-3-pyridin-3-yl    —H-pyrazol-5-yl]methyl}glycyltyrosinamide;-   N-[(1-butyl-3-pyridin-3-yl-1H-pyrazol-5-yl)methyl]-beta-alanyltyrosinamide;-   N-(3-{[(1-butyl-3-pyridin-3-yl-1H-pyrazol-5-yl)methyl]amino}benzoyl)tyrosinamide;-   N-[3-({[1-(4-tert-butylphenyl)-3-pyridin-4-yl-1H-pyrazol-5-yl]methyl}amino)benzoyl]tyrosinamide;-   N-({1-[(1-butyl-3-pyridin-3-yl-1H-pyrazol-5-yl)methyl]piperidin-4-yl}carbonyl)tyrosinamide;-   N-[(1-{[1-(4-tert-butylphenyl)-3-pyridin-3-yl-1H-pyrazol-5-yl]methyl}piperidin-4-yl)carbonyl]tyrosinamide;-   N-2—{[1-(4-tert-butylphenyl)-3-pyridin-3-yl-1H-pyrazol-5-yl]methyl}-N    1-[2-(4-hydroxyphenyl)ethyl]glycinamide;-   N-3-[(1-butyl-3-pyridin-3-yl-1H-pyrazol-5-yl)methyl]-N    1-[2-(4-hydroxyphenyl)ethyl]-beta-alaninamide;-   4-{[(1-butyl-3-pyridin-3-yl-1H-pyrazol-5-yl)methyl]amino}-N-[2-(4-hydroxyphenyl)ethyl]benzamide;    or an optically active isomer, racemate or tautomer thereof, and/or    a pharmaceutically acceptable salts thereof.

Additional preferred compound include:

-   N-({3-[1-(4-tert-butylphenyl)-3-pyridin-4-yl-1H-pyrazol-5-yl]propoxy}acetyl)}tyrosinamide;-   4-[2-({3-[1-(4-tert-butylphenyl)-3-pyridin-4-yl-1H-pyrazol-5-yl]propyl}amino)ethyl]phenol;-   N-{3-[1-(4-tert-butylphenyl)-3-pyridin-4-yl-1H-pyrazol-5-yl]propyl}tyrosinamide;-   N-acetyl-N-{3-[1-(4-tert-butylphenyl)-3-pyridin-4-yl-1H-pyrazol-5-yl]propyl}tyrosinamide;-   N-({3-[1-(4-tert-butylphenyl)-3-pyridin-4-yl-1H-pyrazol-5-yl]propoxy}acetyl)tyrosinamide;-   4-[2-({3-[1-(4-tert-butylphenyl)-3-pyridin-4-yl-1H-pyrazol-5-yl]propyl}amino)ethyl]phenol;-   N-{3-[1-(4-tert-butylphenyl)-3-pyridin-4-yl-1H-pyrazol-5-yl]propyl}tyrosinamide;-   N-acetyl-N-{3-[1-(4-tert-butylphenyl)-3-pyridin-4-yl-1H-pyrazol-5-yl]propyl}tyrosinamide;-   3-[(4-{[1-(4-tert-butylphenyl)-3-pyridin-4-yl-1H-pyrazol-5-yl]amino}butanoyl)amino]-4-(4-hydroxyphenyl)butanamide;-   N-(4-{[1-(4-tert-butylphenyl)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazol-5-yl]amino}butanoyl)tyrosinamide;-   N-(3-{[1-(4-tert-butylphenyl)-3-pyridin-4-yl-1H-pyrazol-5-yl]amino}propyl)tyrosinamide;-   N-acetyl-N-(3-{[1-(4-tert-butylphenyl)-3-pyridin-4-yl-1H-pyrazol-5-yl]amino}propyl)tyrosinamide;-   N-(4-{[1-(4-tert-butylphenyl)-3-(1-oxidopyridin-4-yl)-1H-pyrazol-5-yl]amino}butanoyl)tyrosinamide;-   4-{[1-(4-tert-butylphenyl)-3-pyridin-4-yl-1H-pyrazol-5-yl]amino}-N-[2-(4-hydroxyphenyl)ethyl]butanamide;-   4-{2-[(4-{[1-(4-tert-butylphenyl)-3-pyridin-4-yl-1H-pyrazol-5-yl]amino}butyl)amino]ethyl}phenol;-   N-(4-{[1-(4-tert-butylphenyl)-3-pyridin-4-yl-1H-pyrazol-5-yl]amino}butanoyl)-N-(2-hydroxyethyl)tyrosinamide;-   N-(4-{[1-(4-tert-butylphenyl)-3-pyridin-4-yl-1H-pyrazol-5-yl]amino}butanoyl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]tyrosinamide;-   N-(4-{[1-(4-tert-butylphenyl)-3-pyridin-3-yl-1H-pyrazol-5-yl]amino)}butanoyl)tyrosinamide;-   N-(4-{[1-(4-tert-butylphenyl)-3-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-1H-pyrazol-5-yl]amino}butanoyl)tyrosinamide;-   (3R)-3-[(4-{[1-(4-tert-butylphenyl)-3-pyridin-3-yl-1H-pyrazol-5-yl]amino}butanoyl)amino]-4-(4-hydroxyphenyl)butanamide;-   N-(3-{[1-(4-tert-butylphenyl)-3-pyridin-3-yl-1H-pyrazol-5-yl]amino}propyl)tyrosinamide;-   N-acetyl-N-(3-{[1-(4-tert-butylphenyl)-3-pyridin-3-yl-1H-pyrazol-5-yl]amino}propyl)tyrosinamide;-   N-(4-{[1-(4-tert-butylphenyl)-3-(1-oxidopyridin-3-yl)-1H-pyrazol-5-yl]amino}butanoyl)tyrosinamide;-   4-{[1-(4-tert-butylphenyl)-3-pyridin-3-yl-1H-pyrazol-5-yl]amino}-N-[2-(4-hydroxyphenyl)ethyl]butanamide;-   4-{2-[(4-{[1-(4-tert-butylphenyl)-3-pyridin-3-yl-1H-pyrazol-5-yl]amino}butyl)amino]ethyl}phenol;-   N-(4-{[1-(4-tert-butylphenyl)-3-pyridin-3-yl-1H-pyrazol-5-yl]amino}butanoyl)-N-(2-hydroxyethyl)tyrosinamide;-   N-(4-{[1-(4-tert-butylphenyl)-3-pyridin-3-yl-1H-pyrazol-5-yl]amino}butanoyl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]tyrosinamide;-   N-(4-{[1-(4-tert-butylphenyl)-3-pyridin-3-yl-1H-pyrazol-5-yl]oxy}butanoyl)tyrosinamide;    or an optically active isomer, racemate or tautomer thereof, and/or    a pharmaceutically acceptable salts thereof.

Substituted pyrazole compounds of the invention are useful for treatmentof infertility in male and female mammals, particularly humans.Therapeutic methods of the invention in general comprise administeringan effective amount of one or more substituted pyrazole compounds asdisclosed herein to a mammal in need thereof, such as a mammal suspectedof suffering from infertility, particularly a human suspected ofsuffering from infertility. Compounds of the invention will be usefulfor treatment of infertility conditions currently treated with FSHand/or LH, including female infertility and male spermatogenesisdisorders.

Additionally, in contrast to current protein therapeutics such as FSH,compounds of the invention can be administered orally and withoutextensive medical specialist supervision.

Preferred compounds of the invention exhibit good agonist activity instandard Follicle Stimulating Hormone (FSH) assays, such as the assay ofExample 9 which follows.

It also has been found that substituted pyrazole compounds of theinvention exhibit good inhibition activity against phosphodiesterasePDE4, adenosine transporters, and prostanoid receptors. Accordingly,methods are provided for treatment of diseases and disorders associatedwith phosphodiesterase PDE4, adenosine transporters, and prostanoidreceptors, which methods in general comprise administration of aneffective amount of one or more substituted pyrazole compounds to apatient (e.g. mammal, such as human or other primate) in need of suchtreatment.

The invention also provides pharmaceutical compositions that compriseone or more substituted pyrazole compounds of the invention and asuitable carrier for the compositions. Other aspects of the inventionare disclosed infra.

DETAILED DESCRIPTION OF THE INVENTION

We have now discovered that substituted pyrazole compounds, includingcompounds of the above Formulae I, I′, IA, IB, IC, ID, IE and IF, thatare useful for treatment of infertility in mammals, including female andmale humans.

Suitable alkyl substituent groups of compounds of the invention (whichincludes compounds of Formulae I, I′, IA, IB, IC, ID, IE and IF asdefined above) typically have from 1 to about 12 carbon atoms, morepreferably 1 to about 8 carbon atoms, still more preferably 1, 2, 3, 4,5, or 6 carbon atoms. As used herein, the term alkyl unless otherwisemodified refers to both cyclic and noncyclic groups, although of coursecyclic groups will comprise at least three carbon ring members.Preferred alkenyl and alkynyl groups of compounds of the invention haveone or more unsaturated linkages and typically from 2 to about 12 carbonatoms, more preferably 2 to about 8 carbon atoms, still more preferably2, 3, 4, 5, or 6 carbon atoms. The terms alkenyl and alkynyl as usedherein refer to both cyclic and noncyclic groups, although straight orbranched noncyclic groups are generally more preferred. Preferred alkoxygroups of compounds of the invention include groups having one or moreoxygen linkages and from 1 to about 12 carbon atoms, more preferablyfrom 1 to about 8 carbon atoms, and still more preferably 1, 2, 3, 4, 5or 6 carbon atoms. Preferred alkylthio groups of compounds of theinvention include those groups having one or more thioether linkages andfrom 1 to about 12 carbon atoms, more preferably from 1 to about 8carbon atoms, and still more preferably 1, 2, 3, 4, 5, or 6 carbonatoms. Preferred alkylsulfinyl groups of compounds of the inventioninclude those groups having one or more sulfoxide (SO) groups and from 1to about 12 carbon atoms, more preferably from 1 to about 8 carbonatoms, and still more preferably 1, 2, 3, 4, 5, or 6 carbon atoms.Preferred alkylsulfonyl groups of compounds of the invention includethose groups having one or more sulfonyl (SO₂) groups and from 1 toabout 12 carbon atoms, more preferably from 1 to about 8 carbon atoms,and still more preferably 1, 2, 3, 4, 5 or 6 carbon atoms. Preferredaminoalkyl groups include those groups having one or more primary,secondary and/or tertiary amine groups, and from 1 to about 12 carbonatoms, more preferably 1 to about 8 carbon atoms, still more preferably1, 2, 3, 4, 5, or 6 carbon atoms. Secondary and tertiary amine groupsare generally more preferred than primary amine moieties. Suitableheteroaromatic groups of compounds of the invention contain one or moreN, O or S atoms and include, e.g., coumarinyl including 8-coumarinyl,quinolinyl including 8-quinolinyl, pyridyl, pyrazinyl, pyrimidyl, furyl,pyrrolyl, thienyl, thiazolyl, oxazolyl, oxidizolyl, triazole,imidazolyl, indolyl, benzofuranyl and benzothiazole. Suitableheteroalicyclic groups of compounds of the invention contain one or moreN, O or S atoms and include, e.g., tetrahydrofuranyl, thienyl,tetrahydropyranyl, piperidinyl, morpholino and pyrrolidinyl groups.Suitable carbocyclic aryl groups of compounds of the invention includesingle and multiple ring compounds, including multiple ring compoundsthat contain separate and/or fused aryl groups. Typical carbocyclic arylgroups of compounds of the invention contain 1 to 3 separate or fusedrings and from 6 to about 18 carbon ring atoms. Specifically preferredcarbocyclic aryl groups include phenyl; naphthyl including 1-naphthyland 2-naphthyl; biphenyl; phenanthryl; anthracyl; and acenaphthyl.Substituted carbocyclic groups are particularly suitable includingsubstituted phenyl, such as 2-substituted phenyl, 3-substituted phenyl,4-substituted phenyl, 2,3-substituted phenyl, 2,4-substituted phenyl,and 2,4-substituted phenyl; and substituted naphthyl, including naphthylsubstituted at the 5, 6 and/or 7 positions.

Suitable aralkyl groups of compounds of the invention include single andmultiple ring compounds, including multiple ring compounds that containseparate and/or fused aryl groups. Typical aralkyl groups contain 1 to 3separate or fused rings and from 6 to about 18 carbon ring atoms.Preferred aralkyl groups include benzyl and methylenenaphthyl(—CH₂-naphthyl), and other carbocyclic aralkyl groups, as discussedabove.

Suitable heteroaralkyl groups of compounds of the invention includesingle and multiple ring compounds, including multiple ring compoundsthat contain separate and/or fused heteroaromatic groups, where suchgroups are substituted onto an alkyl linkage. More preferably, aheteroaralkyl group contains a heteroaromatic group that has 1 to 3rings, 3 to 8 ring members in each ring and from 1 to 3 hetero (N, O orS) atoms, substituted onto an alkyl linkage. Suitable heteroaromaticgroups substituted onto an alkyl linkage include e.g., coumarinylincluding 8-coumarinyl, quinolinyl including 8-quinolinyl, pyridyl,pyrazinyl, pyrimidyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl,oxidizolyl, triazole, imidazolyl, indolyl, benzofuranyl andbenzothiazole.

Suitable heteroalicyclicalkyl groups of compounds of the inventioninclude single and multiple ring compounds, where such groups aresubstituted onto an alkyl linkage. More preferably, aheteroalicylicalkyl group contains at least one ring that has 3 to 8ring members from 1 to 3 hetero (N, O or S) atoms, substituted onto analkyl linkage. Suitable heteroalicyclic groups substituted onto an alkyllinkage include e.g. tetrahydrofuranyl, thienyl, tetrahydropyranyl,piperidinyl, morpholino and pyrrolidinyl groups.

As discussed above, particularly preferred X linker groups are alkylene,particularly having 4 or 5 chain carbons, such as —CH₂CH₂CH₂CH₂— and—CH₂CH₂CH₂CH₂CH₂—. X linker groups may one contain one or morecarbon-carbon double or triple bonds in the chain, i.e. a alkenylene,alkynylene, heteroalkenylene or heteroalkynylene linkage. Suchunsaturated X groups typically contain 1, 2 or 3 carbon-carbon multiplebonds, more typically 1 or 2 carbon-carbon multiple bonds. An X groupthat is heteroalkylene, heteroalkenylene, or heteroalkynylene containsone or more N, O or S atoms in the linker chain, more typically 1 or 2N, O or S atoms in the chain. An X linker group also preferably may becarbocyclic aryl or a heteroaromatic group, particularly 3-10 memberedrings or fused rings, more particularly 4, 5 and 6 membered rings withzero, one or more N, O, or S atoms such as optionally substituted o-,m-, p-phenyl, pyridyl, furyl, thiophenyl and pyrrolidinyl rings.

As discussed above, R, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, X, Y and Z groups areoptionally substituted. A “substituted” R, R¹, R², R³, R⁴, R⁵, R⁶, R⁷,X, Y and Z group or other substituent may be substituted by other thanhydrogen at one or more available positions, typically 1 to 3 or 4positions, by one or more suitable groups such as those disclosedherein. Suitable groups that may be present on a “substituted” R, R¹,R², R³, R⁴, R⁵, R⁶, R⁷, X, Y and Z group or other substituent includee.g. halogen such as fluoro, chloro, bromo and iodo; cyano; hydroxyl;nitro; azido; alkanoyl such as a C₁₋₄ alkanoyl group such as acyl andthe like; carboxamido; alkyl groups including those groups having 1 toabout 12 carbon atoms, or 1, 2, 3, 4, 5, or 6 carbon atoms; alkenyl andalkynyl groups including groups having one or more unsaturated linkagesand from 2 to about 12 carbon, or 2, 3, 4, 5 or 6 carbon atoms; alkoxygroups having those having one or more oxygen linkages and from 1 toabout 12 carbon atoms, or 1, 2, 3, 4, 5 or 6 carbon atoms; aryloxy suchas phenoxy; alkylthio groups including those moieties having one or morethioether linkages and from 1 to about 12 carbon atoms, or 1, 2, 3, 4, 5or 6 carbon atoms; alkylsulfinyl groups including those moieties havingone or more sulfinyl linkages and from 1 to about 12 carbon atoms, or 1,2, 3, 4, 5, or 6 carbon atoms; alkylsulfonyl groups including thosemoieties having one or more sulfonyl linkages and from 1 to about 12carbon atoms, or 1, 2, 3, 4, 5, or 6 carbon atoms; aminoalkyl groupssuch as groups having one or more N atoms and from 1 to about 12 carbonatoms, or 1, 2, 3, 4, 5 or 6 carbon atoms; carbocyclic aryl having 6 ormore carbons, particularly phenyl (e.g. an R group being a substitutedor unsubstituted biphenyl moiety); aralkyl having 1 to 3 separate orfused rings and from 6 to about 18 carbon ring atoms, with benzyl beinga preferred group; aralkoxy having 1 to 3 separate or fused rings andfrom 6 to about 18 carbon ring atoms, with O-benzyl being a preferredgroup; or a heteroaromatic or heteroalicyclic group having 1 to 3separate or fused rings with 3 to about 8 members per ring and one ormore N, O or S atoms, e.g. coumarinyl, quinolinyl, pyridyl, pyrazinyl,pyrimidyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl,indolyl, benzofuranyl, benzothiazolyl, tetrahydrofuranyl,tetrahydropyranyl, piperidinyl, morpholino and pyrrolidinyl.

Preferred carbocyclic or heteroaromatic ring substituents of compoundsof the invention include halogen (F, Cl, Br and I; hydroxyl; azido;optionally substituted alkyl having 1 to about 12 carbons such asmethyl, ethyl, propyl and butyl and branched groups such as isopropyl,sec-butyl and tert-butyl, and including halogenated alkyl, particularlyfluoro-alkyl having 1 to about 6 carbon atoms; optionally substitutedalkoxy having 1 to about 12 carbons such as methoxy, ethoxy, propoxy andbutoxy, and including halogenated alkoxy, particularly fluoro-alkoxyhaving 1 to about 6 carbon atoms; optionally substituted alkylthiohaving 1 to about 6 carbons such as methylthio and ethylthio; optionallysubstituted alkylsulfinyl having 1 to about 6 carbons such asmethylsulfinyl (—S(O)CH₃) and ethylsulfinyl (—S(O)CH₂CH₃); optionallysubstituted alkylsulfonyl having 1 to about 6 carbons such asmethylsulfonyl (—S(O)₂CH₃) and ethylsulfonyl (—S(O)₂CH₂CH₃); andoptionally substituted arylalkoxy such as benzyloxy (C₆H₅CH₂O—).

It should be understood that alkoxy, alkylthio, alkylsulfinyl,alkylsulfonyl and aminoalkyl substituent groups described above includegroups where a hetero atom is directly bonded to a ring system, such asa carbocyclic aryl group or a heteroalicyclic or heteroaromatic group,as well as groups where a hetero atom of the group is spaced from suchring system by an alkylene linkage, e.g. of 1 to about 4 carbon atoms.

Specifically preferred compounds of the invention include the followingdepicted compounds, and pharmaceutically acceptable salts of thesecompounds. Results (EC₅₀ values, expressed as [μM) for certain compoundsin the FSH assay of Example 9 are set forth immediately right of thedepicted compound structure.

A particularly preferred compound of the invention is the following:

Compounds of the invention can be readily prepared. For instance,substituted pyrazoles suitable as starting reagents are commerciallyavailable. Generally preferred are pyrazoles having a 3- and/or5-position non-hydrogen substituent that can be further functionalizedto provide a desired compound of the invention. The pyrazole ring can bereadily substituted with desired moieties by known ring additionreactions to provide R¹, R² and R³ substituents. For instance,non-hydrogen R² and R³ substituents can be provided byFriedel-Crafts-type reactions or Suzuki coupling reactions. See alsoU.S. Pat. Nos. 5,986,104; 5,744,493; and 5,486,618, for procedures toprepare substituted pyrazoles.

Suitable pyrazoles for use to prepare compounds of the invention alsomay be readily synthesized. For example, pyrazole reagents may besynthesized by e.g. reaction of a β-dicarbonyl compound with thecorresponding substituted hydrazine or the reaction of the dianion of amethyl hydrazone with the corresponding acid chlorid or acid anhydride.For extensive description of pyrazoles synthesis, see Handbook ofHeterocyclic Chemistry, 2^(nd) edition, A. R. Katritzky and A. F.Pozharskii, Pergamon, 2000 or Comprehensive Heterocyclic Chemistry III,A. R. Katritzky, C. W. Rees, E. F. V. Scriven, 1^(st) Edition, 1996).

Substituted pyrazole compounds of the invention also may be readilyprepared by combinatorial synthetic procedures. For discussions ofcombinatorial procedures, see, e.g., I. Chaiken et al, MolecularDiversity and Combinatorial Chemistry, (ACS, 1996); B. Bunn, TheCombinatorial Index, (Academic Press 1998). See also A. Marzinzik etal., Tetrahedron Letters, 37(7):1003-1006 (1996); Marzinzik et al., J.Org. Chem., 63: 723-727 (1998); and Marzinzik et al: WO 9815532 A119980416 for a solid phase combinatorial synthesis of pyrazoles. Seealso the examples which follow, for exemplary preferred syntheses ofpyrazole compounds of the invention.

More particularly, compounds of the invention including specificregio-isomers can be suitably prepared by combinatorial syntheticprocedures as outlined in the following exemplary Schemes 1, 2 (examplesof mixture of isomers) and 3 (as an example of specific regio isomer).It should be appreciated that the compounds shown in the followingSchemes are exemplary only, and a variety of other compounds can beemployed in a similar manner as described below. Additionally, while insome instances the Schemes detail certain preferred reaction conditions,it will be understood that alternate conditions also may be suitable.

Thus, as depicted in Scheme 1 above, resin bound amine 1 is reacted witha protected amino acid to provide 2 which is reacted with a keto-acid toprovide methyl ketone 4. That methyl ketone is reacted with asubstituted ester (provides R² substituent of Formula I) in the presenceof strong base to yield the di-ketone 5. The adjacent keto groups withinterposed methylene react with a hydrazine to provide the substitutedpyrazole as regio isomeric mixtures 6A and 6B.

Scheme 2 above depicts another route for combinatorial synthesis ofcompounds of the invention. Briefly, resin bound aldehyde 7 isfunctionalized to give secondary amine 8, which is then reacted with aketo-acid to provide tertiary amine 9 with methyl ketone functionality.Reaction with an ester in the presence of a strong base provide compound10 having adjacent keto groups with interposed methylene that can bereacted with a hydrazine to provide substituted pyrazole 11 and itsisomer. Treatment with strong acid releases the pyrazole 12 from theresin.

Scheme 3 above depicts a selective synthesis of specific regioisomer bycombinatorial method. The resin bound methyl ketone 13 on reaction withan appropriate aldehyde in presence of Li(OH) results in α,β-unsaturatedketone 14, which on further reaction with hydrazine results in aspecific regio isomer 15, which can be released from the resin supportin the presence of acid to provide pyrazole 16.

Scheme 4 above depicts the synthesis by combinatorial methods ofpyrazole libraries containing a heteroatom on the side chain,particularly compounds of Formulae I, I′ and IA where R¹ and R² are asdefined above for Formulae I, I′, and IA, R³ is H, X is heteroalkylenechain and Y is CO and Z is tyrosine. It should be recognized that whileall the reactions shown depict tyrosine as the amino acid (Z=Tyr), byusing the appropriate amino acid in the first coupling step other aminoacid derivatives may be prepared. In the scheme W is C₁-C₄ alkyl or 1,3-or 1,4 phenyl radical. All of the reactions shown depict standardcoupling reactions which are known to those skilled in the art. Thepyrazoles with carboxylic acid or carboxaldehyde in the 3 (or 5)position may be prepared by standard literature procedures as depictedbelow.

As already mentioned, compounds of the invention including specificregioisomers can be prepared by solution phase synthetic procedures asoutlined in the following exemplary Schemes 5 and 6.

Compounds of general formula 20 where R¹ and R² have the same definitionas in Formula I can be obtained by reaction of β-diketoalcohol 19 withsuitable hydrazine as depicted in scheme 5. This procedure is apreferred one as it gives rise to a better regioselectivity in favor ofthe 20-B pyrazole regioisomer (see W. V. Murray, Tetrahedron Lett., 34,p.1863,1993). The hydroxyalkyl pyrazole thus obtained can be oxidizedand reacted with an amine or amino-acid ZNH₂ where Z is defined as inFormula I using standard amidation conditions (HATU or EDC/HOAT/DIEA forexample) to give compounds 21. Homologation by one or two carbons usingmethods well known to those skilled in the art followed by an amidationstep can provide compounds 22.

As an example of such transformation, the hydroxyalkyl derivative 19 canbe treated first with iodine in presence of triphenylphosphine andimidazole, then with the anion of tert-butyloxyacetate and finally withtrifluoroacetic acid to give the corresponding carboxylic acid.Compounds of formula 22 where n=3 can be obtained from such carboxylicacid by coupling with appropriate amine or amino acid ZNH₂ usingstandard conditions (as HATU or EDC/HOAT/DIEA).

A second preferred synthetic method for obtaining pyrazoles of thepresent invention is described in scheme 6. It involves the preparationof hydrazone 24 from an acetyl derivative 23 where R¹ and R² have thesame definition as in Formula I and the appropriate hydrazine. Thedianion of the hydrazone is then reacted with an anhydride (RCO)₂O togive the pyrazole 25 where R is (X)_(m), —(Y)_(n)-Z defined as inFormula I or a synthetic precursor which can be easily transformed to(X)_(m)-(Y)_(n)-Z by methods well known to those skilled in the art. Anexample of the conditions that can be used for such transformation canbe found in S. R. Stauffer, Y. Huang, C. J. Coletta, R. Tedesco, J. A.Katzenellenbogen, Biorg. Med. Chem. 2001, 9, 141-150.

In the case of compounds of Formula IC above, suitable methods forpreparation include those exemplified in the following Schemes 7 and 8.

As showed in Scheme 7 above, compounds of general formula 29 and 30wherein R¹, R² and Z are defined as in Formula I above, A is O or NH andq is a number between 1 and 6, may be obtained by alkylation of anintermediate such as 28 with a reactant such as L-(CH₂)_(q)—NH—P whereinL is a leaving group (like OMs, OTs, Cl, Br or I) and P an appropriateprotecting group. After appropriate protection/deprotection steps, theintermediate thus obtained can be submitted to standard amidationconditions well known by those skilled in the art. Depending on thenature of A, intermediate 28 can be obtained by reaction with suitablehydrazine R¹NHNH₂ either from β-ketoester 26 if A is 0 or β-keto-nitrileif A is NH. Examples of specific conditions for those reactions can befound in PCT Int. Appl. 9712884 and M. J. Fray, D. J. Bull, M. Kinns, J.Chem. Research (S), p.11 (1992).

Some compounds of Formula I-C above can be easily obtained fromintermediates 20-A and B (see Scheme 5) using synthetic methods wellknown by those skilled in the art. Scheme 8 below illustrates one ofthose possible methods yielding to compounds 32-A and B wherein R¹, R²and Z are defined as in Formula I. It should be appreciated that themethods shown in scheme 7 and 8 are exemplary only and that a variety ofother methods can be employed to obtained compounds of Formula I-C.

As discussed above, the present invention includes methods for treatinginfertility in male and female mammals, such as primates, particularlyhumans. Compounds of the invention will be useful for treatment ofinfertility conditions currently treated with FSH and/or LH, includingfemale infertility and male spermatogenesis disorders.

The therapeutic methods of the invention generally compriseadministration of an effective amount of one or more compounds of theinvention to a subject including a mammal, such as a primate, especiallya human, in need of such treatment.

Typical candidates for treatment in accordance with the methods of theinvention persons suffering from or suspected of suffering frominfertility. See the Merck Manual, vol. 2, pages 12-17 (16th ed.) foridentification of patients suffering from or suspected of infertility,which in the case of humans, can include failure to conceive within oneyear of unprotected intercourse.

The treatment methods of the invention may be particularly beneficialfor female mammals suffering from an ovulatory disorder. Additionally,compounds of the invention can be administered to females undergoingassisted reproductive treatments such as in-vitro fertilization, e.g. tosimulate follicular development and maturation. Compounds of theinvention also can be administered to males to facilitate adequatespermatogenesis.

The treatment methods of the invention also will be useful for treatmentof infertility in mammals other than humans, such as horses andlivestock e.g. cattle, sheep, cows and the like.

Compounds of the invention may be administered as a “cocktail”formulation, i.e. coordinated administration of one or more compounds ofthe invention together with one or more other active therapeutics,particularly one or more other known fertility agents. For instance, oneor more compounds of the invention may be administered in coordinationwith a regime of Follicle Stimulating Hormone and/or Leutinizing Hormonesuch as Gonal-F, Metrodin HP or Pergonal.

The compounds of this invention can be administered by a variety ofroutes, such as orally or by injection, e.g., intramuscular,intraperitoneal, subcutaneous or intravenous injection, or topicallysuch as transdermally, vaginally and the like. Compounds of theinvention may be suitably administered to a subject in the protonatedand water-soluble form, e.g., as a pharmaceutically acceptable salt ofan organic or inorganic acid, e.g., hydrochloride, sulfate,hemi-sulfate, phosphate, nitrate, acetate, oxalate, citrate, maleate,mesylate, etc.

Compounds of the invention can be employed, either alone or incombination with one or more other therapeutic agents as discussedabove, as a pharmaceutical composition in mixture with conventionalexcipient, i.e., pharmaceutically acceptable organic or inorganiccarrier substances suitable for oral, parenteral, enteral or topicalapplication which do not deleteriously react with the active compoundsand are not deleterious to the recipient thereof. Suitablepharmaceutically acceptable carriers include but are not limited towater, salt solutions, alcohol, vegetable oils, polyethylene glycols,gelatin, lactose, amylose, magnesium stearate, talc, silicic acid,viscous paraffin, perfume oil, fatty acid monoglycerides anddiglycerides, petroethral fatty acid esters, hydroxymethyl-cellulose,polyvinylpyrrolidone, etc. The pharmaceutical preparations can besterilized and if desired mixed with auxiliary agents, e.g., lubricants,preservatives, stabilizers, wetting agents, emulsifiers, salts forinfluencing osmotic pressure, buffers, colorings, flavorings and/oraromatic substances and the like which do not deleteriously react withthe active compounds.

For oral administration, pharmaceutical compositions containing one ormore substituted pyrazole compounds of the invention may be formulatedas e.g. tablets, troches, lozenges, aqueous or oily suspensions,dispersible powders or granules, emulsions, hard or soft capsules,syrups, elixers and the like. Typically suitable are tablets, dragees orcapsules having talc and/or carbohydrate carrier binder or the like, thecarrier preferably being lactose and/or corn starch and/or potatostarch. A syrup, elixir or the like can be used wherein a sweetenedvehicle is employed. Sustained release compositions can be formulatedincluding those wherein the active component is protected withdifferentially degradable coatings, e.g., by microencapsulation,multiple coatings, etc.

For parenteral application, e.g., sub-cutaneous, intraperitoneal orintramuscular, particularly suitable are solutions, preferably oily oraqueous solutions as well as suspensions, emulsions, or implants,including suppositories. Ampules are convenient unit dosages.

For topical applications, formulations may be prepared in a topicalointment or cream containing one or more compounds of the invention.When formulated as an ointment, one or more compounds of the inventionsuitably may be employed with either a paraffinic or a water-misciblebase. The one or more compounds also may be formulated with anoil-in-water cream base. Other suitable topical formulations includee.g. lozenges and dermal patches.

It will be appreciated that the actual preferred amounts of activecompounds used in a given therapy will vary according to the specificcompound being utilized, the particular compositions formulated, themode of application, the particular site of administration, etc. Optimaladministration rates for a given protocol of administration can bereadily ascertained by those skilled in the art using conventionaldosage determination tests conducted with regard to the foregoingguidelines. See also Remington's Pharmaceutical Sciences. In general, asuitable effective dose of one or more compounds of the invention,particularly when using the more potent compound(s) of the invention,will be in the range of from 0.01 to 100 milligrams per kilogram ofbodyweight of recipient per day, preferably in the range of from 0.01 to20 milligrams per kilogram bodyweight of recipient per day, morepreferably in the range of 0.05 to 4 milligrams per kilogram bodyweightof recipient per day. The desired dose is suitably administered oncedaily, or several sub-doses, e.g. 2 to 4 sub-doses, are administered atappropriate intervals through the day, or other appropriate schedule.Such sub-doses may be administered as unit dosage forms, e.g.,containing from 0.05 to 10 milligrams of compound(s) of the invention,per unit dosage.

The entire text of all documents cited herein are incorporated byreference herein. The following non-limiting examples are illustrativeof the invention.

EXAMPLE 1 Synthesis ofN-(5-[1-(4-tert-butylphenyl)-5-pyridin-3-yl-1H-pyrazol-3-yl]pentanoyl)tyrosinamide(1-A) andN-(5-[1-(4-tert-butylphenyl)-3-pyridin-3-yl-1H-pyrazol-5-yl]pentanoyl)tyrosinamide(1-B) on solid phase

Rink-amide resin (30 g, loading=0.65 mmol/g) was shaken in a largepeptide vessel in a 20% piperidine solution in DMF (200 mL) for 30 min.This operation was repeated 2 times. The resin was then washed with DMF(3×), NMP (2×), MeOH (2×) and DCM (2×) and dried under vacuum for 30min. The deprotected resin was transferred into a 1 L bottle and shakenfor 27 h in a solution containing Fmoc-Tyr(tBu)—OH (90 g), HATU (74 g)and DIEA (60 mL) in 360 mL of DMF. After this time, the resin wastransferred into a peptide vessel, washed with DMF (3×), DCM (2×), MeOH(2×), DMF (1×), DCM (1×) and dried under vacuum for 15 min. It was thenshaken in a 20% piperidine solution in DMF (200 mL) for 30 min 3 times,washed with DMF (3×), NMP (2×), MeOH (2×), DCM (2×) and dried undervacuum for 15 min. For the next step, the resin was transferred againinto a 1 L bottle and shaken for 48 h in a solution of acetylvalericacid (28.1 g), HATU (74.1 g) and DIEA (66 mL) in DMF (360 mL). Samewashing procedure as for the preceding coupling step was followed. Theresin was dried under vacuum and divided into two portions of about 32 g(portion I) and 31 g (portion 2).

Portion 1 was transferred into a IL bottle flushed with nitrogencontaining a solution of methylnicotinate (40 g) in 200 mL of DMA.Sodium hydride 95% (70 g) was then added in small portions into themixture with constant nitrogen flushing. The bottle was placed in an icebath and agitated by hand until the hydrogen release had stopped. It wasthen heated at 85° C. for 2 hours with occasional hand agitation. Afterthat time, the mixture was chilled to room temperature and poured slowlyinto a beaker containing ice and a solution of 15% acetic acid in water.Transfer into a peptide vessel was operated before the standard washingand drying steps. The 18 g of resin thus obtained were poured into a ILbottle containing 4-tert-butylphenylhhydrazine hydrochloride (39.1 g)and DIEA (33.1 mL) in DMA (360 mL) and heated for 24 hours at 80° C. Thebottle was chilled to room temperature and the resin was washed anddried following standard procedure. Finally, it was cleaved with 100 mLof DCM/TFA (2:1) and the residue was concentrated under reducedpressure. It was dissolve in ethyl acetate and washed with slightlybasic solution (pH 8.5-9 obtained with diluted NH₄OH). The organic layerwas dried over magnesium sulfate, filtered and concentrated to give 3.65g of crude (yield ˜70%). This crude contained a mixture of the twopossible pyrazole regioisomers 1A and 1B with a ratio of about 9:1. Thetwo regioisomers were separated by reversed phase HPLC using DELTAPAKC₁₈ column with a linear gradient of 0.1% TFA water/acetonitrile 95:5 to60:40 in one hour.

Structures were assigned by Nuclear Overhauser experiments performed ona JEOL 400 MHz NMR apparatus. There were NOE cross peaks displayedbetween the proton 5 and proton 1 and 4 for isomer A, indicating thatthe phenyl ring is close from the pyridine ring and no NOE effectobserved between those protons for isomer B. Isomer 1-A (more polar):trifluoroacetate salt ofN-(5-[1-(4-tert-butylphenyl)-5-pyridin-3-yl-1H-pyrazol-3-yl]pentanoyl)tyrosinamide

¹H NMR (DMSO): 1.28 (s, 9H), 1.55 (m, 4H), 2.12 (t, J=7.3 Hz, 2H), 2.63(m, 3H), 2.86 (dd, J=5.3 and 13.9 Hz, 1H), 4.35 (m, 1H), 5.60 (brs, 1H),6.61 (s, 1H), 6.62 (d, J=8.8 Hz, 2H), 6.98 (m, 1H), 7.01 (d, J=8.8 Hz,2H), 7.19 (d, J=8.8 Hz, 2H), 7.36 (m, 1H), 7.42 (d, J=8.8 Hz, 2H), 7.51(dd, J=8.1 and 5.1 Hz, 1H), 7.75 (dt, J=8.1 and 2.2 Hz, 1H), 8.52 (dd,J=2.2 and 0.73 Hz, 1H), 8.58 (dd, J=4.9 and 1.5 Hz, 1H).

MS (ESI, pos.): 540 (M+1)

Isomer 1-B (less polar): trifluoroacetate salt ofN-(5-[1-(4-tert-butylphenyl)-3-pyridin-3-yl-1H-pyrazol-5-yl]pentanoyl)tyrosinamide

¹H NMR (DMSO): 1.34 (s, 9H), 1.47 (m, 4H), 2.05 (t, J=9.1 Hz, 2H), 2.61(m, 1H), 2.64 (t, J=6.9 Hz, 2H), 2.84 (m, 1H), 4.34 (m, 1H), 6.30 (brs,1H), 6.59 (d, J=8.4 Hz, 2H), 6.98 (m, 1H), 6.99 (d, J=8.4 Hz, 2H), 7.02(s, 1H), 7.37 (m, 1H), 7.48 (d, J=8.8 Hz, 2H), 7.58 (d, J=8.8 Hz, 2H),7.86 (d, J=8.4 Hz, 1H), 7.92 (dd, J=8.1 and 5.5 Hz, 1H), 8.72 (dt, J=8.4and 1.46 Hz, 1H), 8.76 (dd, J=5.49 and 1.46 Hz, 1H), 9.24 (d, J=2.2 Hz,1H).

MS (ESI, pos.): 540 (M+1)

EXAMPLE 2 Synthesis ofN-(5-[1-(4-tert-butylphenyl)-5-pyridin-4-yl-1H-pyrazol-3-yl]pentanoyl)tyrosinamide(2-A) andN-(5-[1-(4-tert-butylphenyl)-3-pyridin-4-yl-1H-pyrazol-5-yl]pentanoyl)tyrosinamide(2-B)

Those compounds were synthesized from the portion 2 (31 g) of resinobtained in Example 1 above following exactly the same procedure. Allthe reagents and quantities are the same except that methylnicotinatewas replaced by methylisonicotinate. 2.5 g of crude were obtained (48%yield) and contained a mixture of the two possible pyrazole regioisomers2A and 2B with a ratio of about 9:1. The two regioisomers were separatedusing the same conditions as those described in example 1. Thestructures were assigned by analogy with compounds 1A and 1B. Isomer 2-A(more polar): trifluoroacetate salt ofN-(5-[1-(4-tert-butylphenyl)-5-pyridin-4-yl-1H-pyrazol-3-yl]pentanoyl)tyrosinamide

¹H NMR (DMSO): 1.29 (s, 9H), 1.52 (m, 4H), 2.10 (t, J=7.3 Hz, 2H), 2.55(m, 3H), 2.83 (dd, J=4.4 and 14.3 Hz, 1H), 4.35 (m, 1H), 6.61 (d, J=6.6Hz, 2H), 6.77 (s, 1H), 7.00 (s, 1H), 7.01 (d, J=6.9 Hz, 2H), 7.22 (d,J=6.6 Hz, 2H), 7.38 (m, 3H), 7.45 (d, J=6.9 Hz, 2H), 7.88 (d, J=8.4 Hz,1H), 8.63 (d, J=4.8 Hz, 2H), 9.2 (brs, 1H).

MS (ESI, pos.): 540 (M+1)

Isomer 2-B (less polar): trifluoroacetate salt ofN-(5-[1-(4-tert-butylphenyl)-3-pyridin-4-yl-1H-pyrazol-5-yl]pentanoyl)tyrosinamide

¹H NMR (DMSO): 1.34 (s, 9H), 1.43 (m, 4H), 2.04 (t, J=9.1 Hz, 2H), 2.50(m, 1H), 2.64 (m, 2H), 2.83 (dd, J=3.3 and 9.2 Hz,1H), 4.35 (m, 1H),6.58 (d, J=6.9 Hz, 2H), 6.98 (m, 3H), 7.14 (s, 1H), 7.38 (s, 1H), 7.49(d, J=6.9 Hz, 2H), 7.59 (d, J=6.9 Hz, 2H), 7.86 (d, J=8.4 Hz,1H), 8.17(d, J=4.7 Hz, 2H), 8.78 (d, J=4.1 Hz, 2H), 9.2 (brs, 1H).

MS (ESI, pos.): 540 (M+1)

Elemental analysis: C₃₂H₃₇N₅O₃.TFA.1,5H₂O, theoretical: C, 59.99%; H,6.07%: N, 10.29%; experimental: C, 60.12%; H, 5.95%: N, 10.27%.

EXAMPLE 3 Combinatorial Synthesis of Pyrazole Library of the Invention

A library of ˜2500 pyrazoles synthesized via Fmoc/t-Butyl chemistryusing either IRORI AccuTag/Robin technology. 20 microkans each in threeglass bottles containing Fmoc Rink Amide MBHA resin (25 mg, 0.59 mmol/g)were treated with 20% piperidine/DMF (30 mL, 3×30 min) and then rinsedwith DMF and acylated with 0.1 M solution of Fmoc amino acid (3 mmlol)in DMF (30 mL), HATU (3 mmol) and DIEA (6 mmol) at room temperature for16 hours, rinsed with DMF. Fmoc was removed with 20% piperidine/DMF (100mL, 3×30 min), rinsed with DMF. 30 microkans in two glass bottles resinwere acylated with 0.1 M solution of acetyl carboxylic acid (4.5 mmol)in DMF (45 mL), HATU (4.5 mmol) and DIEA (9 mmol) at room temperaturefor 16 hours and then rinsed with DMF. Claisen condensation was carriedout with 30 microkans in two glass bottles with 0.25 M solution of ester(11.25 mmol), 95% NaH (11.25 mmol) in DMA at 90° C. in the oven for 2hours. The microkans were washed (DMA, MeOH, DMF and CH₂CI₂) and driedunder reduced pressure. Cyclization was carried out with 12 microkans in5 glass bottles with 0.125M solution of hydrazine (2.25 mmol), DIEA(2.25 mmol) in DMA (18 mL) at 80° C. in the oven for 24 hours, rinsedand dried under reduced pressure. The final cleavage of resin wascarried out with TFA at 2 hours in the IRORI cleavage block. The residuewas then co-evaporated with CH₃CN under reduced pressure.

All of the crude pyrazoles were analyzed by reversed phase HPLC usingDELTAPAK C₁₈, 5 μM column, eluted with a linear gradient of 0.1% TFA inCH₃CN/water (0% CH₃CN/100% water) to 0.1% TFA in CH₃CN/water (100%CH₃CN/0% water) over a 30 minute period with flow rate of 1.5 mL/minute.The purity of the samples were determined and were essentially found tocontain the pyrazole in 60% purity as a mixture of regioisomers. Themass were confirmed by matrix-assisted laser desorption ionization timeof flight mass spectral analysis (MALDI-TOF, PE Biosystem, Inc.).Generally the pyrazoles gave the mass of MH+ or M+Na+ or withinexperimental error of the calculated value.

EXAMPLE 4 Compound Purification

The crude pyrazoles prepared in Example 3 above were purified byreversed phase HPLC using DELTAPAK C₁₈, 5 M column, eluted with a lineargradient of 0.1% TFA in CH₃CN/water (0% CH₃CN/100% water) to 0.1% TFA inCH₃CN/water (100% CH₃CN/0% water) over a 30 minute period with flow rateof 15 mL/minute. The purity of the samples were determined and wereessentially found to contain one component. The mass were confirmed bymatrix-assisted laser desorption ionization time of flight mass spectralanalysis (MALDI-TOF, PE Biosystem, Inc.). Generally the pyrazoles gavethe mass of MH+ or M+Na+ or within experimental error of the calculatedvalue.

For example, the following compounds were prepared by this procedure:

-   N-{5-[1-(4-tert-butylphenyl)-3-pyridin-2-yl-1H-pyrazol-5-yl]pentanoyl}tyrosinamide,    [M+H]=540;-   N-{5-[1-(4-tert-butylphenyl)-3-pyridin-3-yl-1H-pyrazol-5-yl]pentanoyl}tyrosinamide,    [M+H]=540;-   N-{5-[1-(4-tert-butylphenyl)-5-pyridin-3-yl-1H-pyrazol-3-yl]pentanoyl}tyrosinamide,    [M+H]=540;-   N-{5-[1-(4-tert-butylphenyl)-3-pyridin-4-yl-1H-pyrazol-5-yl]pentanoyl}tyrosinamide,    [M+H]=540;-   N-{5-[1-(4-tert-butylphenyl)-5-pyridin-4-yl-1H-pyrazol-3-yl]pentanoyl}tyrosinamide,    [M+H]=540;-   N-{5-[1-(4-tert-butylphenyl)-3-pyridin-3-yl-1H-pyrazol-5-yl]pentanoyl}-N,N-dimethyltyrosinamide,    [M+H]=554;-   N-[4-(1-butyl-3-isoquinolin-3-yl-1H-pyrazol-5-yl)benzoyl]tyrosinamide,    [M+H]=534;-   N-{5-[1-(4-isopropylphenyl)-3-pyridin-3-yl-1H-pyrazol-5-yl]pentanoyl}tyrosinamide,    [M+H]=526;-   N-{6-[1-(4-isopropylphenyl)-3-pyridin-2-yl-1H-pyrazol-5-yl]hexanoyl}tyrosinamide,    [M+H]=540;-   N-{6-[1-(4-tert-butylphenyl)-3-pyridin-2-yl-1H-pyrazol-5-yl]hexanoyl}-3-hydroxyphenylalaninamide,    [M+H]=554;-   N-[1-(aminocarbonyl)-3-(4-hydroxyphenyl)propyl]-5-[1-(4-tert-butylphenyl)-3-pyridin-2-yl-1H-pyrazol-5-yl]pentanamide,    [M+H]=554;-   N-[5-(1-butyl-3-isoquinolin-3-yl-1H-pyrazol-5-yl)pentanoyl]tyrosinamide,    [M+H]=514;-   N-{6-[1-(4-tert-butylphenyl)-3-pyridin-2-yl-1H-pyrazol-5-yl]hexanoyl}serinamide,    [M+H]=478;-   N-{6-[1-(4-iso-propylphenyl)-3-pyridin-2-yl-1H-pyrazol-5-yl]hexanoyl}serinamide,    [M+H]=464;-   N-{6-[1-(4-iso-propylphenyl)-3-pyridin-2-yl-1H-pyrazol-5-yl]hexanoyl}threonamide,    [M+H]=478;-   N-{5-[1-(4-isopropylphenyl)-3-pyridin-2-yl-1H-pyrazol-5-yl]pentanoyl}tyrosinamide,    [M+H]=526;-   6-[1-(4-tert-butylphenyl)-3-pyridin-2-yl-1H-pyrazol-5-yl]-N-[2-(4-hydroxyphenyl)ethyl]hexanamide,    [M+H]=511;-   N-{6-[1-(4-tert-butylphenyl)-3-pyridin-2-yl-1H-pyrazol-5-yl]hexanoyl}tyrosinamide,    [M+H]=554;-   N-{5-[1-(4-tert-butylphenyl)-3-isoquinolin-3-yl-1H-pyrazol-5-yl]pentanoyl}tyrosinamide,    [M+H]=590;-   N-{6-[1-(4-tert-butylphenyl)-3-isoquinolin-3-yl-1H-pyrazol-5-yl]hexanoyl}tyrosinamide,    [M+H]=604;-   N-{6-[1-(4-tert-butylphenyl)-3-pyridin-2-yl-1H-pyrazol-5-yl]hexanoyl}-N-methyltyrosinamide,    [M+H]=568;-   N-{6-[1-(4-tert-butylphenyl)-3-pyridin-2-yl-1H-pyrazol-5-yl]hexanoyl}-4-(hydroxymethyl)phenylalaninamide,    [M+H]=568;-   4-amino-N-{6-[1-(4-tert-butylphenyl)-3-pyridin-2-yl-1H-pyrazol-5-yl]hexanoyl}phenylalaninamide,    [M+H]=553;-   4-(acetylamino)-N-{6-[1-(4-tert-butylphenyl)-3-pyridin-2-yl-1H-pyrazol-5-yl]hexanoyl}phenylalaninamide,    [M+H]=595;-   4-(aminocarbonyl)-N-{6-[1-(4-tert-butylphenyl)-3-pyridin-2-yl-1H-pyrazol-5-yl]hexanoyl}phenylalaninamide,    [M+H]=581;-   N-butyl-N-{6-[1-(4-tert-butylphenyl)-3-pyridin-2-yl-1H-pyrazol-5-yl]hexanoyl}tyrosinamide,    [M+H]=610;-   N-{6-[1-(4-tert-butylphenyl)-3-pyridin-2-yl-1H-pyrazol-5-yl]hexanoyl}threonamide,    [M+H]=492;-   N-[2-amino-1-(4-hydroxyphenyl)-2-oxoethyl]-6-[1-(4-tert-butylphenyl)-3-pyridin-2-yl-1H-pyrazol-5-yl]hexanamide,    [M+H]=540;-   N-{2-[4-(aminosulfonyl)phenyl]ethyl}-5-[1-(4-tert-butylphenyl)-3-pyridin-2-yl-1H-pyrazol-5-yl]pentanamide,    [M+H]=560;-   N-({5-[1-(4-isopropylphenyl)-3-pyridin-2-yl-1H-pyrazol-5-yl]thien-2-yl}carbonyl)tyrosinamide,    [M+H]=552;-   N-[2-amino-1-(4-hydroxyphenyl)-2-oxoethyl]-4-[1-(4-tert-butylphenyl)-3-pyridin-2-yl-1H-pyrazol-5-yl]benzamide,    [M+H]=546;-   4-[1-(4-tert-butylphenyl)-3-pyridin-2-yl-1H-pyrazol-5-yl]-N-[2-(4-hydroxyphenyl)ethyl]benzamide,    [M+H]=517;-   N-{3-[1-(4-tert-butylbenzyl)-3-isoquinolin-3-yl-1H-pyrazol-5-yl]benzoyl}tyrosinamide,    [M+H]=608;-   N-{5-[1-(4-tert-butylphenyl)-3-pyridin-4-yl-1H-pyrazol-5-yl]pentanoyl}tyrosinamide,    [M+H]=540;-   N-{3-[1-(4-tert-butylbenzyl)-3-pyridin-3-yl-1H-pyrazol-5-yl]benzoyl}tyrosinamide,    [M+H]=574;-   N-{3-[1-(4-tert-butylphenyl)-3-isoquinolin-3-yl-1H-pyrazol-5-yl]benzoyl}tyrosinamide,    [M+H]=610;-   N-[4-(1-butyl-3-isoquinolin-3-yl-1H-pyrazol-5-yl)benzoyl]tyrosinamide,    [M+H]=534;-   N-{3-[1-(4-tert-butylbenzyl)-3-quinolin-3-yl-1H-pyrazol-5-yl]benzoyl}tyrosinamide,    [M+H]=624;-   N-{3-[3-isoquinolin-3-yl-1-(4-propylphenyl)-1H-pyrazol-5-yl]benzoyl}tyrosinamide,    [M+H]=610;-   N-{3-[1-(4-tert-butylphenyl)-3-pyridin-3-yl-1H-pyrazol-5-yl]benzoyl}tyrosinamide,    [M+H]=560;-   N-{4-[1-(4-tert-butylphenyl)-3-pyridin-3-yl-1H-pyrazol-5-yl]benzoyl}tyrosinamide,    [M+H]=560;-   N-{5-[1-(4-tert-butylbenzyl)-3-pyridin-4-yl-1H-pyrazol-5-yl]pentanoyl}tyrosinamide,    [M+H]=554;-   N-{3-[1-(4-tert-butylbenzyl)-3-pyridin-4-yl-1H-pyrazol-5-yl]benzoyl}tyrosinamide,    [M+H]=574;-   N-{5-[1-(4-tert-butylbenzyl)-3-pyridin-3-yl-1H-pyrazol-5-yl]pentanoyl}tyrosinamide,    [M+H]=554;-   N-[3-(1-butyl-3-isoquinolin-3-yl-1H-pyrazol-5-yl)benzoyl]tyrosinamide,    [M+H]=534;-   N-{4-[1-butyl-3-(2-furyl)-1H-pyrazol-5-yl]benzoyl}tyrosinamide,    [M+H]=473;-   N-{5-[1-butyl-3-(2-furyl)-1H-pyrazol-5-yl]pentanoyl}tyrosinamide,    [M+H]=453;-   N-{3-[3-(2-furyl)-1-(4-isopropylphenyl)-1H-pyrazol-5-yl]propanoyl}tyrosinamide,    {M+H]=487;-   N-(4-{1-(4-tert-butylphenyl)-3-[3-(dimethylamino)phenyl]-1H-pyrazol-5-yl}benzoyl)tyrosinamide,    [M+H]=602;-   N-[1-(aminocarbonyl)-3-(4-hydroxyphenyl)propyl]-4-[3-(2-furyl)-1-(4-isopropylphenyl)-1H-pyrazol-5-yl]benzamide,    [M+H]=549;-   N-[1-(aminocarbonyl)-3-(4-hydroxyphenyl)propyl]-5-{1-(4-tert-butylphenyl)-3-[3-(dimethylamino)phenyl]-1H-pyrazol-5-yl}pentanamide,    [M+H]=596;-   N-{5-[1-(4-tert-butylphenyl)-3-(2-furyl)-1H-pyrazol-5-yl]pentanoyl}tyrosinamide,    [M+H]=529;-   N-[1-(aminocarbonyl)-3-(4-hydroxyphenyl)propyl]-4-[3-(2-furyl)-1-pyridin-2-yl-1H-pyrazol-5-yl]benzamide,    [M+H]=508;-   N-(4-{3-[3-(dimethylamino)phenyl]-1-pyridin-2-yl-1H-pyrazol-5-yl}benzoyl)tyrosinamide,    [M+H]=547;-   N-(5-{1-butyl-3-[3-(dimethylamino)phenyl]-1H-pyrazol-5-yl}pentanoyl)    tyrosinamide, [M+H]=506;-   N-(5-{1-(4-tert-butylphenyl)-3-[3-(dimethylamino)phenyl]-1H-pyrazol-5-yl}pentanoyl)tyrosinamide,    [M+H]=582;-   N-[5-(1-butyl-3-quinolin-3-yl-1H-pyrazol-5-yl)pentanoyl]tyrosinamide,    [M+H]=514;-   N-{5-[1-(4-tert-butylphenyl)-3-quinolin-3-yl-1H-pyrazol-5-yl]pentanoyl}tyrosinamide,    [M+H]=590;-   N-[5-(1-butyl-3-quinolin-6-yl-1H-pyrazol-5-yl)pentanoyl]tyrosinamide,    [M+H]=514;-   N-{5-[1-(4-tert-butylphenyl)-3-quinolin-6-yl-1H-pyrazol-5-yl]pentanoyl}tyrosinamide,    [M+H]=590;-   N-{5-[1-(4-tert-butylbenzyl)-3-quinolin-6-yl-1H-pyrazol-5-yl]pentanoyl}tyrosinamide,    [M+H]=604;-   N-[5-(1-hexyl-3-pyrazin-2-yl-1H-pyrazol-5-yl)pentanoyl]tyrosinamide,    [M+H]=493;    N-[(1-butyl-3-pyridin-3-yl-1H-pyrazol-5-yl)methyl]glycyltyrosinamide;    [M+H]=451;-   N-{[1-(4-tert-butylphenyl)-3-pyridin-3-yl-1H-pyrazol-5-yl]methyl}glycyltyrosinamide,    [M+H]=527;-   N-[(1-butyl-3-pyridin-3-yl-1H-pyrazol-5-yl)methyl]-beta-alanyltyrosinamide,    [M+H]=465;-   N-(3-{[(1-butyl-3-pyridin-3-yl-1H-pyrazol-5-yl)methyl]amino}benzoyl)tyrosinamide,    [M+H]=513;-   N-[3-({[1-(4-tert-butylphenyl)-3-pyridin-4-yl-1H-pyrazol-5-yl]methyl}amino)benzoyl]tyrosinamide,    [M+H]=589;-   N-({1-[(1-butyl-3-pyridin-3-yl-1H-pyrazol-5-yl)methyl]piperidin-4-yl}carbonyl)    tyrosinamide, [M+H]=505;-   N-[(1-{[1-(4-tert-butylphenyl)-3-pyridin-3-yl-1H-pyrazol-5-yl]methyl}piperidin-4-yl)carbonyl]tyrosinamide,    [M+H]=581;-   N-2-{[1-(4-tert-butylphenyl)-3-pyridin-3-yl-1H-pyrazol-5-yl]methyl}-N    1-[2-(4-hydroxyphenyl)ethyl]glycinamide; [M+H]=484;-   N-3-[(1-butyl-3-pyridin-3-yl-1H-pyrazol-5-yl)methyl]-N-1-[2-(4-hydroxyphenyl)ethyl]-beta-alaninamide,    [M+H]=422;-   4-{[(1-butyl-3-pyridin-3-yl-1H-pyrazol-5-yl)methyl]amino}-N-[2-(4-hydroxyphenyl)ethyl]benzamide,    [M+H]=470.

EXAMPLE 5 Regioselective Synthesis of Pyrazoles

Commercially available Fmoc-protected rink amide resin (0.7 g) wasdeprotected with 20% piperidine in DMF, rinsed and acylated with 0.5Msolution of Fmoc-amino acid (10 equiv)/HATU (10 equiv)/DIEA (20equiv)overnight in DMF at room temperature, rinsed with DMF. Fmoc group wasremoved with 20% piperidine/DMF and resin was rinsed with DMF, acylatedwith 0.5M solution of acetyl carboxylic acid (10 equiv)/HATU (10equiv)/DIEA (20 equiv) overnight at room temperature, rinsed with DMF.The resin was added with LiOH.H₂O (40 equivalents) in anhydrous DME and40 equivalents of aldehyde was added. The resin was shaken for 16 hrsand filtered and washed with glacial acetic acid, DMA, I-PrOH, DCM. Theresulted (x,p-unsaturated ketone was cyclized to pyrazole by adding the0.5M solution of 4-t-butyl phenyl hydrazine in DMSO and allowing thereaction to proceed for 16 hrs. Resin was washed with DMA, i-PrOH, DCMand dried before treating with TFA release the desired pyrazole productfrom the resin. The crude product was purified by preparative HPLC.

EXAMPLE 6 Solution Phase Synthesis

Synthesis ofN-(3-[1-(4-tert-butylphenyl)-5-pyridin-3-yl-1H-pyrazol-3-yl]propanoyl)tyrosinamide(3-A) and N-(3-[1-(4-tert-butylphenyl)-3-pyridin-3-yl-1H-pyrazol-5-yl]propanoyl)tyrosinamide (2-B)

Compound 3-A: 6-Hydroxy-1-(3-pyridinyl)-hexan-1,3-dione

A solution of y-butyrolactone (1.92 mL, 2.15 g, 25.0 mmol), 60%suspension of sodium hydride in mineral oil (300 mg, 7.50 mmol) and3-acetylpyridine (551 PL, 606 mg, 5.00 mmol) in dimethylsulfoxyde (4 mL)and tetrahydrofuran (36 mL) was stirred overnight at 25° C. Ethanol (4mL) was added to destroy excess sodium hydride and the reaction mixturewas adsorbed on silica gel (10 g). Flash chromatography on silica gel(75 g), eluting with DCM/MeOH/NH₄OH (96/4/1), gave 1.14 g of a yellowoil containing compound 3-A (0.62 g, 60%).

¹H NMR (CDCl₃):69.00 (d, J=1.8 Hz, 1H), 8.65 (dd, J=4.8, 1.5 Hz, 1H),8.09 (dt, J=8.1, 2.2 Hz, 1H), 7.34 (dd, J=8.1, 4.8 Hz, 1H), 6.17 (s,1H), 3.64 (t, J=6.2, 2H), 2.5 (m, 2H), 1.88 (t, J=6.2, 2H).

MS (ESI, +): 208 (M+1)

Compound 3′-B:3-{1-(4-tert-butylphenyl)-5-pyridin-3-yl-1H-pyrazol-3′-yl}propan-1-oland3-{1-(4-tert-butylphenyl)-3-pyridin-3-yl-1H-pyrazol-5-yl}propan-1-ol.

A solution of compound 3-A (370 mg, 1.79 mmol) and4-tert-butylphenylhydrazine hydrochloride (359 mg, 1.79 mmol) inabsolute methanol (10 mL) was stirred overnight at 25° C. The reactionmixture was then adsorbed on silica gel (5 g) and purified by flashchromatography on silica gel (60 g), eluting with DCM/MeOH/NH₄OH(96/4/1), to afford 709 mg of a yellow oil containing the pyrazole 3-B(two regioisomers, 452 mg, 75%, ratio 24/76) and DMSO. An aliquot ofthis mixture was purified with preparative HPLC deltapack C18 column,using a gradient of water/acetonitrile from 95/5 to 50/50 in 60 min, togive pure samples of the two regioisomers.

More Polar Regioisomer:

¹H NMR (CDCl₃): δ 8.80 (s, 1H), 8.76 (d, J=5.0 Hz, 1H), 7.95 (d, J=8.1),7.70 (dd, J=8.1, 5.4 Hz, 1H), 7.43 (d, J=7.7 Hz, 2H), 7.16 (d, J=8.1 Hz,2H),6.60 (s, 1H), 4.48 (t, J=6.0 Hz, 2H), 2.88 (t, J=7.3 Hz, 2H), 2.23(pent., J=7.0 Hz, 2H), 1.32 (s, 9H).

MS (ESI, +): 336 (M+1)

Less polar regioisomer (partially salified with trifluoroacetate)

¹H NMR (CDCl₃): δ 9.30 (d, J=9.2 Hz, 1H), 8.87 (d, J=8.4 Hz, 1H), 8.73(t, J=5.8 Hz, 1H), 7.9 (m, 1H), 7.5 (m, 2H), 7.3 (m, 2H), 6.81 (s,0.6H), 6.77 (s, 0.4H), 4.36 (t, J=6.0 Hz, 1.2H), 3.71 (t, J=6.0 Hz,0.8H),2.83 (t, J=7.7 Hz, 1.2H), 2.81 (t, J=8.0 Hz), 2.10 (pent., J=7.7Hz, 1.2H), 1.92 (pent., J=7.3 Hz, 0.8H), 1.36 (s, 9H).

MS (ESI, +): 336(M+1)

Compound 3-C:3-{1-(4-tert-butylphenyl)-5-pyridin-3-yl-1H-pyrazol-3-yl}propanoic acidand 3-{1-(4-tert-butylphenyl)-3-pyridin-3-yl-1H-pyrazol-5-yl}propanoicacid

To a solution of pyrazoles 3-B (168 mg, 0.500 mmol) in acetone (4 mL)was added a solution of 2N H₂Cr₂O₇ (0.75 mL) at 10° C. The mixture wasstirred for 1 h, and the solution was decanted away from solid,concentrated and filtrated through a C₁₈ column with a mixture 95/5 ofwater/acetonitrile. Once concentrated, the residue was engaged directlyinto the next step.

MS (ESI, +) 350 (M+1)

Compound 3N-(3-[1-(4-tert-butylphenyl)-5-pyridin-3-yl-1H-pyrazol-3-yl]propanoyl)tyrosinamide(3-A) andN-(3-[1-(4-tert-butylphenyl)-3-pyridin-3-yl-1H-pyrazol-5-yl]propanoyl)tyrosinamide(3-B)

To a solution of compounds 3-C (150 mg, 0.43 mmol),1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (104 mg,0.54 mmol), HOAT (73 mg, 0.54 mmol) and N,N-diisopropylethylamine (229μL, 174 mg, 1.35 mmol) in N,N-dimethylformamide (3 mL) was addedO-(tert-butyl)tyrosinamide (128 mg, 0.54 mmol). The reaction mixture wasstirred overnight at 25° C., then diluted with a solution of 0.1Nammonia (30 mL) and extracted with ethyl acetate (3×25 mL). The combinedorganic phases are dried over magnesium sulfate, filtrated andconcentrated. The crude thus obtained was dissolved in dichloromethane(5 mL) and stirred overnight at room temperature in presence oftrifluoroacetic acid (2 mL). The reaction mixture was concentrated andinjected on HPLC deltapack C18 column for purification using a lineargradient of 0.1% TFA water/acetonitrile from 95/5 to 60/40 in 60 min togive the two possible regioisomers whose structures were assigned byanalogy with compounds 1-A and 1-B.

N-(3-[1-(4-tert-butylphenyl)-5-pyridin-3-yl-1H-pyrazol-3-yl]propanoyl)tyrosinamide(3-A):

¹H NMR (DMSO): δ 8.54 (s, 1H), 8.45 (s, 1H), 8.03 (d, J=8.4 Hz, 1H),7.66 (d, J=8.1 Hz, 1H), 7.42 (m, 3H), 7.38 (s, 1H), 7.16 (d, J=7.3 Hz,2H), 7.01 (d, J=8.1 Hz, 2H), 7.00 (s, 1H), 6.61 (d, J=7.0 Hz, 2H), 6.56(s, 1H), 4.38 (m, 1H), 2.90-2.75 (m, 3H), 2.64 (dd, J=13.9, 9.9 Hz, 1H),2.50 (m, 2H), 1.28 (s, 9H).

MS (ESI, +): 512 (M+1)

N-(3-[1-(4-tert-butylphenyl)-3-pyridin-3-yl-1H-pyrazol-5-yl]propanoyl)tyrosinamide(3-B):

¹HNMR (DMSO): δ 9.15 (s, 1H), 8.68 (s, 1H), 8.51 (d, J=7.3 Hz, 1H), 8.13(d, J=8.5 Hz, 1H), 7.76 (m, 1H), 7.58 (d, J=8.4 Hz, 2H), 7.47 (d, J=8.4Hz, 2H), 7.44 (s, 1H), 7.02 (s, 1H), 6.99 (d, J=8.4 Hz, 2H), 6.93 (s,1H), 6.58 (d, J=8.4 Hz, 2H), 4.34 (m, 1H), 2.88-2.79 (m, 3H), 2.63 (dd,J=14.3, 10.2 Hz, 1H), 2.50 (m, 3H) 1.34 (s, 9H).

MS (ESI, +): 512 (M+1)

EXAMPLE 7 Synthesis of the trifluoroacetate salt ofN-(4-{[1-(4-tert-butylphenyl)-3-pyridin-4-yl-1H-pyrazol-5-yl]amino}butanoyl)tyrosinamide7

Compound 7a: :N-[1-(4-tert-butylphenyl)-3-pyridin-4-yl-1H-pyrazol-5-yl]-trifluoroacetamide

-   N-[1-(4-tert-butylphenyl)-3-pyridin-4-yl-1H-pyrazol-5-yl]-amine    (1.05 g, 3.60 mmol) obtained following literature procedure (J.    Chem. Research(S), 10,1992) was dissolved in pyridine,    trifluoroacetic anhydride (530 μl, 3.78 mmol) was then slowly added    and the mixture was stirred under nitrogen atmosphere at room    temperature for 12 h. Pyridine was concentrated under reduced    pressure and the resulting brown oil was dissolved in Ethyl acetate    and washed twice with water and twice with brine. The organic layer    was dried over magnesium sulfate, filtered and concentrated to give    1.17 g of crude material. This crude was purified by flash    chromatography with DCM/MeOH/NH₄OH (95/5/1 then 85/5/1). 387 mg    (yield=28%) of pure material was isolated beside degradations    products.

¹H NMR (CDCl₃): 1.34 (s, 9H), 7.21 (s, 1H), 7.41 (d, J=8.8 Hz, 2H), 7.56(d, J=8.7 Hz, 2H), 7.72 (m, 2H), 8.47 (m, 1H), 8.58 (m, 2H).

MS (ESI, +): 389 (M+1)

Compound 7b: 4-{[1-(4-tert-butylphenyl)-3-pyridin-4-yl-1H-pyrazol-5-yl](trifluoroacetyl)amino}butanoic acid

A solution of compound 7a (387 mg, 1.0 mmol) and ethyl-4-bromobutyrate(780 mg, 4 mmol) in acetone (15 mL) was heated under reflux in presenceof potassium carbonate (553 mg, 4.0 mmol) and potassium iodide (183 mg,1.1 mmol). After 48 h, the reaction was completed, acetone was removedunder reduced pressure and the crude was dissolved in Ethyl acetate,washed with water and brine (2×) and finally dried over magnesiumsulfate, filtrated and concentrated.

The crude (930 mg) was purified by flash chromatography withDCM/MeOH/NH₄OH 90/10/1. 354 mg of a nice yellow powder were isolated(yield=70%).

¹HNMR (CDCl₃): 1.25 (t, J=6.2 Hz, 3H), 1.35 (s, 9H), 2.12 (m, 2H), 2.35(t, J=6.6 Hz, 2H), 4.12 (q, J=6.2 Hz, 2H), 4.34 (t, J=7.3 Hz, 2H), 7.21(s, 1H), 7.45 (d, J=7.7 Hz, 2H), 8.03 (m, 4H), 8.31 (d, J=6.2 Hz, 2H).

MS (ESI, +): 503 (M+1)

Compound 7c: Potassium salt of4-{[1-(4-tert-butylphenyl)-3-pyridin-4-yl-1H-pyrazol-5-yl]amino}butanoicacid

A solution of ester 7b (234 mg, 0.47 mmol) in methanol/water, (1:1, 10mL) was heated under reflux for 8 h in presence of potassium carbonate(195 mg, 1.41 mmol). The mixture was then concentrated under reducedpressure, toluene was added and removed under reduced pressure. Thecrude thus obtained (398 mg) was analyzed (see below) and directlyengaged in the next step.

¹H NMR (DMSO): 1.34 (s, 9H), 1.82 (t, J=6.2 Hz, 2H), 2.01 (t, J=6.3 Hz,2H), 4.55 (t, J=6.6 Hz, 2H), 5.75, s, 1H), 6.32 (s, 1H), 7.58 (s, 4H),8.33 (d, J=5.1 Hz, 2H), 8.98 (d, J=5.5 Hz, 2H).

MS (ESI, +): 379 (M+1)

Compound 7d: O-(tert-butyl)tyrosinamide

N-Fmoc-O-tert-butyl-tyrosine (3.27 g, 7.12 mmol) was dissolved indioxane (15 mL). Ammonium hydrogenocarbonate (732 mg, 9.26 mmol),di-tert-butyl-dicarbonate (2.02 g, 9.26 mmol) and pyridine (0.4 mL) wereadded and the mixture was stirred under nitrogen atmosphere at roomtemperature for 12 h. It was then diluted with ethyl acetate and theorganic phase was washed with brine (2×), 5% sulfuric acid (1×) andbrine again. It was dried over magnesium sulfate and concentrated. Thecrude thus obtained (3.17 g) was dissolved in dichloromethane (50 mL)and diethylamine (10 mL). The mixture was stirred at room temperaturefor 12 h, concentrated under reduced pressure and purified by flashchromatography with DCM/MeOH/NH₄OH (95/5/1 then 90/10/1) to give 1.37 gof the desired compound (yield=81%).

¹H NMR (CDCl₃): 1.32 (s, 9H), 2.66 (dd, J=9.5 and 13.6 Hz, 1H), 3.20(dd, J=3.7 and 13.9 Hz, 1H), 3.57 (dd, J=4.0 and 9.5 Hz, 1H), 5.40 (m,1H), 6.93 (d, J=7.0 Hz, 2H), 7.06 (m, 1H), 7.10 (d, J=7.3 Hz, 2H).

MS (ESI, +): 237 (M+1)

Compound 7e:N-(4-{[1-(4-tert-butylphenyl)-3-pyridin-4-yl-1H-pyrazol-5-yl]amino}butanoyl)-O-(tert-butyl)tyrosinamideCompound 7c (170 mg, 0.45 mmol) was reacted with1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (104 mg,0.54 mmol), HOAT (73 mg, 0.54 mmol) and diisopropylamine (2301, 1.35mmol) in dimethylformamide (6 mL). O-(tert-butyl)tyrosinamide 7d (118mg, 0.50 mmol) was then added and the reaction mixture was stirred atroom temperature under nitrogen atmosphere. After completion of thereaction (48 h), it was diluted with ethyl acetate and water. The twolayers were separated and it appeared that the product was essentiallyin the aqueous phase. This latter was concentrated and injected on HPLCdeltapack C18 column for purification using a gradient ofwater/acetonitrile from 95/5 to 40/60 in 60 min. 96 mg of pure compoundwas isolated after lyophilisation (yield=36%).

¹H NMR (CDCl₃) 1.25 (s, 9H), 1.35 (s, 9H), 2.20-2.43 (m, 4H), 2.90 (t,J=9.9 Hz, 1H), 3.18 (brd, J=10.6 Hz, 1H), 4.27-4.52 (m, 7H), 6.20 (s,1H), 6.84 (d, J=8.0 Hz, 2H), 7.15 (d, J=8.0 Hz, 2H), 7.50 (m, 4H), 8.18(m, 2H), 8.29 (m, 1H), 8.53 (m, 1H).

MS (ESI, +): 597 (M+1)

Compound 7: Compound 7e (89 mg, 0.15 mmol) was dissolved indichloromethane and trifluoroacetic acid was added. The mixture wasstirred overnight and concentrated to give 103 mg of a brown solid(quantitative yield).

¹H NMR (DMSO): 0.82 (m, 2H), 1.33 (s, 9H), 2.13 (m, 2H), 2.60 (m, 1H),2.86 (m, 1H), 4.19-4.38 (m, 3H), 5.81 (m, 1H), 6.32 (s, 1H), 6.63 (d,J=6.6 Hz, 2H), 7.00 (d, J=6.6 Hz, 2H), 7.01 (s, 1H), 7.45 (s, 1H), 7.58(brs, 4H), 7.69 (m, 2H), 8.02 (d, J=8.4 Hz, 1H), 8.34 (d, J=5.1 Hz, 2H),8.85 (d, J=5.1 Hz, 2H), 9.16 (s, 1H).

EXAMPLE 8 CHO Parental Cells Assay

The following compound 1-B was demonstrated to be hFSHR specific bytesting it on untransfected CHO parental cells.

Briefly CHO parental cells were plated in 96 well packard view plates5×10⁴ cells/well in serum containing media. After 20 hours the cellswere confluent. The wells were washed with serum free assay medium(containing 0.1 mM MIX) and pre-incubated for 15 minutes in this medium.Compound 1 and forskolin (positive control) were added and the cellswere incubated for an additional one hour. The cells were lysed andintracellular cAMP was measured using the Amersham direct one stepcAMP-RIA kit according to the manufacturers directions. Compound 1showed no response over background.

These cells were shown to have no response over background tostimulation with a 10⁻⁷ (M) dose of rhFSH in a previous experiment. Inboth experiments forskolin showed a five fold response over background.

EXAMPLE 9 FSH Assay Method

All compounds were stored in 96-well deepwell plates in DMSO at anominal concentration of 10 mM (assuming perfect synthesis and yields).Compounds were screened for agonist activity at the FSH receptor usingthe recombinant FSH receptor stably transfected and expressed in ChineseHamster Ovary Cells (CHO cells) essentially as described in the work byKelton, et al. (Molecular and Cellular Endocrinology, 1992, 89,141-151). Since the FSH receptor is known to act via a G-protein (Gs) toactivate adenylyl cyclase and hence raise intracellular levels of cAMPthe high throughput screening (HTS) assay used a gene reporter systemconsisting of the cAMP response element coupled upstream to the reportergene which, in this case was the enzyme luciferase. Thus an agonist atthe FSH receptor increases cAMP in the cell which results in activationof the CREB (cAMP) response element binding protein). This moleculeinteracts with the CRE element on the gene in the nucleus and results inincreased transcription of the genes downstream of this element. Thesubstrate for the enzyme (Packard Instrument Company 800 ResearchParkway, Meriden, Conn. 06450, USA) was added to the cells afterappropriate incubation with the compounds or FSH and the amount ofluciferase expressed was measured by quantitating the luminescenceproduced by the enzyme using a TopCount scintillation/luminescencecounter running in single photon counting mode. A compound which actedas an agonist at the receptor should produce light from the treatedcells in proportion to its concentration within the incubation.Luminescence should be saturable at high concentrations of the compound.

EXAMPLE 10 HTS Primary Assay

The compounds, in deepwell plates (Master plates) as indicated abovewere loaded on the robotic deck along with the appropriate number ofassay plates and daughter plates. A 10 μl aliquot from each master platewas transferred to the corresponding daughter plate and 90 μl of DME/F12was added and mixed within each well. 20 μl was then removed from thedaughter plate and dispensed into the assay plate. After addition of analiquot of FSH (equivalent to an EC100 response for this hormone [Finalconcentration of 5c-11 M]) to each of three wells on the plate, 80 ul ofmedia (DME/F¹²+2% serum) and 100 ul aliquot of cells (4×10⁵/ml in thesame media) were added and the plate incubated at 37° C. for 3 hrs 30min. At this time the plate was removed from the incubator and media ineach well was aspirated and the cells adhering to the bottom of theplate washed with 300 ul PBS containing 1 mM ca²⁺ and 1 mM Mg²⁺. The PBSwas aspirated and 100 ul PBS added to each well. 100 ul of Lucite(prepared as described by the manufacturer) was added to each well andthe plate was shaken gently for 40 seconds prior to placement in theTopCount plate reader. After allowing 3.5 minutes for the plate todark-adapt within the machine, the amount of luminescence generated wasquantiated using Single Photon Counting mode. The data was transmittedelectronically from the TopCount to the robot processing computerterminal and was renamed with an ID corresponding to the original masterplate ID. Data was evaluated using an Excel macro and compounds showingactivity comparable to that produced by an EC100 of FSH itself werefurther analyzed in the same assay at differing concentrations. LDR(log-dose-response) curves were generated for these compounds in CHOcells containing the FSH receptor and these curves were also comparedwith those in either cells expressing a different Gs linked receptor orin cells lacking any transfected receptor and these curves were alsocompared with those in either cells expressing a different Gs linkedreceptor or in cells lacking any transfected receptor.

Compounds which showed receptor specificity and activity at lowconcentrations were progressed to secondary assays which includeddose-response curves in Y1 cells co-expressing the human FSH receptor orin isolated rat granulosa cells.

EXAMPLE 11 Secondary Assay; Rat Granulosa Cell Assay

A primary rat granulosa cell bioassay for follicle stimulating hormone(FSH) was used. Conversion of testosterone to estradiol in the presenceof low nanomolar concentrations of FSH was detected using this assay. Inthis in vitro assay, conversion of androstendione to estrogen bygranulosa cells in the presence of FSH was measured using a RIA.

Granulosa cell culture and FSH stimulation: Cells were plated at 5000,8,000 and 20,000 cells/well/200 μl of GAB medium on poly-D-lysine coated96-well tissue culture plates. Plates were incubated at 37° C. in a 5%CO/95% air incubator for 3 days. Cultures were washed prior tostimulation with FSH or LH. 50 μl of 4× concentrations of rhFSH, rhLH orforskolin was added to the cultures. To define the range of the doseresponse curve the rhFSH was diluted so that the final concentration onthe cells was between 10⁻⁷ to 10⁻¹⁵ (M) with three doses per log at 1, 2and 5. Forskolin was diluted so that the final concentration on thecells was 1 μM. Cells were incubated @ 37° C. in 5% CO₂. Three dayslater, cell supernatants were collected and diluted 1:100 in GAB mediumfor measurement of estradiol by RIA. The RIA was performed according tomanufacturer directions except that an estradiol standard was preparedin absolute ethanol at 100 ng/ml and then further diluted in GAB medium,instead of kit buffer. The concentration of hormone was plotted on theX-axis against the amount of estradiol produced by the cells on theY-axis using Origin graphics software.

The invention has been described in detail with reference to preferredembodiments thereof. However, it will be appreciated that those skilledin the art, upon consideration of this disclosure, may makemodifications and improvements within the spirit and scope of theinvention.

1. A method for treating infertility in a mammal, comprisingadministering to a mammal suspected of infertility a therapeuticallyeffective amount of a substituted pyrazole compound.
 2. A method ofclaim 1 wherein pyrazole is substituted at 1 or 2 ring positions bynon-hydrogen substituents.
 3. A method of claim 1 wherein the pyrazoleis substituted at the 5-position by a non-hydrogen substituent.
 4. Amethod of claim 1 wherein the pyrazole is substituted at both the 3- and5-positions by non-hydrogen substituents.
 5. A method of claims 1wherein the pyrazole compound is of the following Formula I:

wherein R¹ is hydrogen; optionally substituted alkyl; optionallysubstituted alkenyl; optionally substituted alkynyl; optionallysubstituted carbocyclic aryl; optionally substituted aralkyl; optionallysubstituted heteroaromatic or heteroalicyclic group; or optionallysubstituted heteroaralkyl or heteroalicyclicalkyl group; R² and R³ areeach independently hydrogen, halogen, optionally substituted alkyl;optionally substituted alkenyl; optionally substituted alkynyl;optionally substituted alkoxy; optionally substituted alkylthio;optionally substituted alkylsulfinyl; optionally substitutedalkylsulfonyl; optionally substituted carbocyclic aryl; optionallysubstituted aralkyl; optionally substituted heteroaromatic orheteroalicyclic group; or optionally substituted heteroaralkyl orheteroalicyclicalkyl group; X is optionally substituted alkylene;optionally substituted alkenylene; optionally substituted alkynylene;optionally substituted heteroalkylene; optionally substitutedheteroalkenylene; optionally substituted heteroalkynynylene; or X isoptionally alicyclic, optionally substituted carbocyclic aryl;optionally substituted heteroalicyclic, optionally substitutedheteroaromatic, optionally substituted heteroaralkyl, or optionallysubstituted heteroalicyclicalkyl group; Y is optionally substitutedamino; optionally substituted methylene; carbonyl; or sulfonyl; Z is anoptionally substituted alkylamine; an amino acid; or a glycine; m is 0or 1; n is 0 or 1; and pharmaceutically acceptable salts thereof.
 6. Amethod of claims 1 wherein the pyrazole compound is of the followingFormula I′:

wherein R¹, R² and R³ are each independently hydrogen; optionallysubstituted alkyl; optionally substituted alkenyl; optionallysubstituted alkynyl; optionally substituted alkoxy; optionallysubstituted alkylthio; optionally substituted alkylsulfinyl; optionallysubstituted alkylsulfonyl; optionally substituted carbocyclic aryl;optionally substituted aralkyl; optionally substituted heteroaromatic orheteroalicyclic group; or optionally substituted heteroaralkyl orheteroalicyclicalkyl; X is optionally substituted alkylene; optionallysubstituted alkenylene; optionally substituted alkynylene; optionallysubstituted heteroalkylene; optionally substituted heteroalkenylene;optionally substituted heteroalkenynylene; optionally substitutedalicyclic; optionally substituted carbocyclic aryl; optionallysubstituted aralkyl; optionally substituted heteroaromatic; optionallysubstituted heteroalicyclic group; optionally substituted heteroaralkyl;or optionally substituted heteroalicyclicalkyl group; Y is optionallysubstituted amino; optionally substituted methylene; carbonyl; orsulfonyl; Z is an optionally substituted alkylamine; an amino acid; or aglycine; m and n are each independently 0 or 1; and pharmaceuticallyacceptable salts thereof.
 7. A method of claims 1 wherein the pyrazolecompound is of the following Formula IA:

wherein R¹ is optionally substituted alkyl, optionally substitutedalkenyl; optionally substituted alkynyl; optionally substitutedcarbocyclic aryl; optionally substituted aralkyl; optionally substitutedheteroaromatic; optionally substituted heteroalicyclic group; optionallysubstituted heteroaralkyl; or optionally substitutedheteroalicyclicalkyl group; R² and R³ are each independently hydrogen;optionally substituted alkyl; optionally substituted alkenyl; optionallysubstituted alkynyl; optionally substituted alkoxy; optionallysubstituted alkylthio; optionally substituted alkylsulfinyl; optionallysubstituted alkylsulfonyl; optionally substituted carbocyclic aryl;optionally substituted aralkyl; optionally substituted heteroaromatic orheteroalicyclic group; or optionally substituted heteroaralkyl orheteroalicyclicalkyl; X is optionally substituted alkylene; optionallysubstituted alkenylene; optionally substituted alkynylene; optionallysubstituted heteroalkylene; optionally substituted heteroalkenylene;optionally substituted heteroalkenynylene; optionally substitutedalicyclic; optionally substituted carbocyclic aryl; optionallysubstituted aralkyl; optionally substituted heteroaromatic; optionallysubstituted heteroalicyclic group; optionally substituted heteroaralkyl;or optionally substituted heteroalicyclicalkyl group; Y is optionallysubstituted amino; optionally substituted methylene; carbonyl; orsulfonyl; Z is an optionally substituted alkylamine; an amino acid; or aglycine; m and n are each independently 0 or 1; and pharmaceuticallyacceptable salts thereof.
 8. A method of claims 1 wherein the pyrazolecompound is of the following Formula IB:

wherein R¹ and R² are each independently optionally substituted alkyl;optionally substituted alkenyl; optionally substituted alkynyl;optionally substituted carbocyclic aryl; optionally substituted aralkyl;optionally substituted heteroaromatic or heteroalicyclic group; oroptionally substituted heteroaralkyl or heteroalicyclicalkyl group; X isoptionally substituted alkylene; optionally substituted alkenylene;optionally substituted alkynylene; optionally substitutedheteroalkylene; optionally substituted heteroalkenylene; optionallysubstituted heteroalkenynylene; optionally substituted alicyclic;optionally substituted carbocyclic aryl; optionally substituted aralkyl;optionally substituted heteroaromatic; optionally substitutedheteroalicyclic group; optionally substituted heteroaralkyl; oroptionally substituted heteroalicyclicalkyl group; Y is optionallysubstituted amino; optionally substituted methylene; carbonyl; orsulfonyl; -Z is an optionally substituted alkylamine; an amino acid; ora glycine; m and n are each independently 0 or 1; and pharmaceuticallyacceptable salts thereof.
 9. A method of claims 1 wherein the pyrazolecompound is of the following Formula IC:

wherein R¹ is optionally substituted alkyl; optionally substitutedalkenyl; optionally substituted alkynyl; optionally substitutedcarbocyclic aryl; optionally substituted aralkyl; optionally substitutedheteroaromatic or heteroalicyclic group; or optionally substitutedheteroaralkyl or heteroalicyclicalkyl group; R² is halogen; optionallysubstituted alkyl; optionally substituted alkenyl; optionallysubstituted alkynyl; optionally substituted alkoxy; optionallysubstituted alkylthio; optionally substituted alkylsulfinyl; optionallysubstituted alkylsulfonyl; optionally substituted carbocyclic aryl;optionally substituted aralkyl; optionally substituted heteroaromatic orheteroalicyclic group; or optionally substituted heteroaralkyl orheteroalicyclicalkyl group; R³ is hydrogen; halogen; optionallysubstituted alkyl; optionally substituted alkenyl; optionallysubstituted alkynyl; optionally substituted alkoxy; optionallysubstituted alkylthio; optionally substituted alkylsulfinyl; optionallysubstituted alkylsulfonyl; optionally substituted carbocyclic aryl;optionally substituted aralkyl; optionally substituted heteroaromatic orheteroalicyclic group; or optionally substituted heteroaralkyl orheteroalicyclicalkyl group; Y is optionally substituted amino;optionally substituted methylene; carbonyl; or sulfonyl; Z is anoptionally substituted alkylamine; an amino acid; or a glycine; n is 0or 1; X is optionally substituted heteroalkylene; optionally substitutedheteroalkenylene; optionally substituted heteroalkynylene; andpharmaceutically acceptable salts thereof.
 10. A method of claims 1wherein the compound is of the following Formula ID

wherein R¹ is hydrogen; optionally substituted alkyl; optionallysubstituted alkenyl; optionally substituted alkynyl; optionallysubstituted carbocyclic aryl; optionally substituted aralkyl; optionallysubstituted heteroaromatic or heteroalicyclic group; or optionallysubstituted heteroaralkyl or heteroalicyclicalkyl group; R² is halogen;optionally substituted alkyl; optionally substituted alkenyl; optionallysubstituted alkynyl; optionally substituted alkoxy; optionallysubstituted alkylthio; optionally substituted alkylsulfinyl; optionallysubstituted alkylsulfonyl; optionally substituted carbocyclic aryl;optionally substituted aralkyl; optionally substituted heteroaromatic orheteroalicyclic group; or optionally substituted heteroaralkyl orheteroalicyclicalkyl group; R³ is hydrogen; halogen; optionallysubstituted alkyl; optionally substituted alkenyl; optionallysubstituted alkynyl; optionally substituted alkoxy; optionallysubstituted alkylthio; optionally substituted alkylsulfinyl; optionallysubstituted alkylsulfonyl; optionally substituted carbocyclic aryl;optionally substituted aralkyl; optionally substituted heteroaromatic orheteroalicyclic group; or optionally substituted heteroaralkyl orheteroalicyclicalkyl group; X is optionally substituted alkylene;optionally substituted alkenylene; optionally substituted alkynylene;optionally substituted heteroalkylene; optionally substitutedheteroalkenylene; optionally substituted heteroalkynynylene; or X isoptionally alicyclic, optionally substituted -carbocyclic aryl;optionally substituted heteroalicyclic, optionally substitutedheteroaromatic, optionally substituted heteroaralkyl, or optionallysubstituted heteroalicyclicalkyl group; Y is optionally substitutedamino; optionally substituted methylene; carbonyl; or sulfonyl; Z is anoptionally substituted alkylamine; an amino acid; or a glycine; n is 0or 1; R⁵ and R⁶ are independently hydrogen, optionally substitutedalkyl; optionally substituted alkenyl; optionally substituted alkynyl;optionally substituted carbocyclic aryl; optionally substituted aralkyl;optionally substituted heteroaromatic or heteroalicyclic group; oroptionally substituted heteroaralkyl or heteroalicyclicalkyl group; Q isomitted or is —CH₂)_(p)—CO-A-R⁷ wherein p is 0, 1 or 2; A is O or NH andR⁷ is independently hydrogen, optionally substituted alkyl; optionallysubstituted alkenyl; optionally substituted alkynyl; optionallysubstituted carbocyclic aryl; optionally substituted aralkyl; optionallysubstituted heteroaromatic or heteroalicyclic group; or optionallysubstituted heteroaralkyl or heteroalicyclicalkyl group; andpharmaceutically acceptable salts thereof.
 11. A method of claims 1wherein the compound is of the following Formula IE

wherein R¹ is optionally substituted alkyl; optionally substitutedalkenyl; optionally substituted alkynyl; optionally substitutedcarbocyclic aryl; optionally substituted aralkyl; optionally substitutedheteroaromatic or heteroalicyclic group; or optionally substitutedheteroaralkyl or heteroalicyclicalkyl group; R² is halogen; optionallysubstituted alkyl; optionally substituted alkenyl; optionallysubstituted alkynyl; optionally substituted alkoxy; optionallysubstituted alkylthio; optionally substituted alkylsulfinyl; optionallysubstituted alkylsulfonyl; optionally substituted carbocyclic aryl;optionally substituted aralkyl; optionally substituted heteroaromatic orheteroalicyclic group; or optionally substituted heteroaralkyl orheteroalicyclicalkyl group; R³ is halogen, optionally substituted alkyl;optionally substituted alkenyl; optionally substituted alkynyl;optionally substituted alkoxy; optionally substituted alkylthio;optionally substituted alkylsulfinyl; optionally substitutedalkylsulfonyl; optionally substituted carbocyclic aryl; optionallysubstituted aralkyl; optionally substituted heteroaromatic orheteroalicyclic group; or optionally substituted heteroaralkyl orheteroalicyclicalkyl group; Y is optionally substituted amino;optionally substituted methylene; carbonyl; or sulfonyl; Z is anoptionally substituted alkylamine; an amino acid; or a glycine; n is 0or 1; X is optionally substituted heteroalkylene; optionally substitutedheteroalkenylene; optionally substituted heteroalkynylene; R⁵ and R⁶ areindependently hydrogen; optionally substituted alkyl; optionallysubstituted alkenyl; optionally substituted alkynyl; optionallysubstituted carbocyclic aryl; optionally substituted aralkyl; optionallysubstituted heteroaromatic or heteroalicyclic group; or optionallysubstituted heteroaralkyl or heteroalicyclicalkyl group; and Q isomitted or is —CH₂)_(p)—CO-A-R⁷ wherein p is 0, 1 or 2; A is O or NH andR⁷ is independently hydrogen, optionally substituted alkyl; optionallysubstituted alkenyl; optionally substituted alkynyl; optionallysubstituted carbocyclic aryl; optionally substituted aralkyl; optionallysubstituted heteroaromatic or heteroalicyclic group; or optionallysubstituted heteroaralkyl or heteroalicyclicalkyl group; andpharmaceutically acceptable salts thereof.
 12. A method of claims 1wherein the compound is of the following Formula IF:

wherein R¹ is optionally substituted alkyl; optionally substitutedalkenyl; optionally substituted alkynyl; optionally substitutedcarbocyclic aryl; optionally substituted aralkyl; optionally substitutedheteroaromatic or heteroalicyclic group; or optionally substitutedheteroaralkyl or heteroalicyclicalkyl group; R² is halogen; optionallysubstituted alkyl; optionally substituted alkenyl; optionallysubstituted alkynyl; optionally substituted alkoxy; optionallysubstituted alkylthio; optionally substituted alkylsulfinyl; optionallysubstituted alkylsulfonyl; optionally substituted carbocyclic aryl;optionally substituted aralkyl; optionally substituted heteroaromatic orheteroalicyclic group; or optionally substituted heteroaralkyl orheteroalicyclicalkyl group; R³ is hydrogen; halogen; optionallysubstituted alkyl; optionally substituted alkenyl; optionallysubstituted alkynyl; optionally substituted alkoxy; optionallysubstituted alkylthio; optionally substituted alkylsulfinyl; optionallysubstituted alkylsulfonyl; optionally substituted carbocyclic aryl;optionally substituted aralkyl; optionally substituted heteroaromatic orheteroalicyclic group; or optionally substituted heteroaralkyl orheteroalicyclicalkyl group; Y is optionally substituted amino;optionally substituted methylene; carbonyl; or sulfonyl; Z is anoptionally substituted alkylamine; an amino acid; or a glycine; n is 0or 1; X is optionally alicyclic, optionally substituted carbocyclicaryl; optionally substituted heteroalicyclic, optionally substitutedheteroaromatic, optionally substituted heteroaralkyl, or optionallysubstituted heteroalicyclicalkyl group; R⁵ and R⁶ are independentlyhydrogen, optionally substituted alkyl; optionally substituted alkenyl;optionally substituted alkynyl; optionally substituted carbocyclic aryl;optionally substituted aralkyl; optionally substituted heteroaromatic orheteroalicyclic group; or optionally substituted heteroaralkyl orheteroalicyclicalkyl group; and Q is omitted or is —CH₂)_(p)—CO-A-R⁷wherein p is 0, 1 or 2; A is O or NH and R⁷ is independently hydrogen,optionally substituted alkyl; optionally substituted alkenyl; optionallysubstituted alkynyl; optionally substituted carbocyclic aryl; optionallysubstituted aralkyl; optionally substituted heteroaromatic orheteroalicyclic group; or optionally substituted heteroaralkyl orheteroalicyclicalkyl group; and pharmaceutically acceptable saltsthereof
 13. A method of claims 5 wherein R¹, R² and R³ is other thanhydrogen.
 14. A method of claims 5 wherein R² is other than hydrogen.15. A method of claims 5 wherein R¹ is optionally substituted alkyl oroptionally substituted carbocyclic aryl ore optionally substitutedaryalkyl.
 16. A method of claims 5 wherein R² is optionally substitutedcarbocyclic aryl or optionally substituted heteroaromatic andheteroalicyclic.
 17. A method of claims 5 wherein X is an optionallysubstituted alkylene.
 18. A method of claims 5 wherein X is anoptionally substituted carbocyclic aryl or an optionally substitutedheteroaromatic group.
 19. A method of claims 5 wherein X is anoptionally substituted carbocyclic aryl or an optionally substitutedheteroalkylene group.
 20. A method of claims 5 wherein X is—CH₂CH₂CH₂CH₂— or —CH₂CH₂CH₂CH₂CH₂—.
 21. A method of claims 5 wherein Xis optionally substituted phenyl, optionally substituted phenoxy; oroptionally substituted phenylamino.
 22. A method of claims 5 wherein Zis a phenolic moiety.
 23. A method of claims 5 wherein Z is a tyrosinegroup.
 24. A method for treatment of a subject suffering from orsusceptible to a disease or disorder associated with phosphodiesterasePDE4, adenosine transporters, or prostanoid receptors, comprisingadministering to the mammal a therapeutically effective amount of asubstituted pyrazole compound.
 25. A method of claim 24 wherein thepyrazole compound is of the following Formula I:

wherein R¹ is hydrogen; optionally substituted alkyl; optionallysubstituted alkenyl; optionally substituted alkynyl; optionallysubstituted carbocyclic aryl; optionally substituted aralkyl; optionallysubstituted heteroaromatic or heteroalicyclic group; or optionallysubstituted heteroaralkyl or heteroalicyclicalkyl group; R² and R³ areeach independently hydrogen, halogen, optionally substituted alkyl;optionally substituted alkenyl; optionally substituted alkynyl;optionally substituted alkoxy; optionally substituted alkylthio;optionally substituted alkylsulfinyl; optionally substitutedalkylsulfonyl; optionally substituted carbocyclic aryl; optionallysubstituted aralkyl; optionally substituted heteroaromatic orheteroalicyclic group; or optionally substituted heteroaralkyl orheteroalicyclicalkyl group; X is optionally substituted alkylene;optionally substituted alkenylene; optionally substituted alkynylene;optionally substituted heteroalkylene; optionally substitutedheteroalkenylene; optionally substituted heteroalkynynylene; or X isoptionally alicyclic, optionally substituted carbocyclic aryl;optionally substituted heteroalicyclic, optionally substitutedheteroaromatic, optionally substituted heteroaralkyl, or optionallysubstituted heteroalicyclicalkyl group; Y is optionally substitutedamino; optionally substituted methylene; carbonyl; or sulfonyl; Z is anoptionally substituted alkylamine; an amino acid; or a glycine; m is 0or 1; n is 0 or 1; and pharmaceutically acceptable salts thereof.
 26. Amethod of claim 24 wherein the pyrazole compound is of the followingFormula I′:

wherein R¹, R² and R³ are each independently hydrogen; optionallysubstituted alkyl; optionally substituted alkenyl; optionallysubstituted alkynyl; optionally substituted alkoxy; optionallysubstituted alkylthio; optionally substituted alkylsulfinyl; optionallysubstituted alkylsulfonyl; optionally substituted carbocyclic aryl;optionally substituted aralkyl; optionally substituted heteroaromatic orheteroalicyclic group; or optionally substituted heteroaralkyl orheteroalicyclicalkyl; X is optionally substituted alkylene; optionallysubstituted alkenylene; optionally substituted alkynylene; optionallysubstituted heteroalkylene; optionally substituted heteroalkenylene;optionally substituted heteroalkenynylene; optionally substitutedalicyclic; optionally substituted carbocyclic aryl; optionallysubstituted aralkyl; optionally substituted heteroaromatic; optionallysubstituted heteroalicyclic group; optionally substituted heteroaralkyl;or optionally substituted heteroalicyclicalkyl group; Y is optionallysubstituted amino; optionally substituted methylene; carbonyl; orsulfonyl; Z is an optionally substituted alkylamine; an amino acid; or aglycine; m and n are each independently 0 or 1; and pharmaceuticallyacceptable salts thereof.
 27. A method of claims 1 wherein the compoundis selected from the group consisting of:N-{5-[1-(4-tert-butylphenyl)-3-pyridin-2-yl-1H-pyrazol-5-yl]pentanoyl}tyrosinamide;N-{5-[1-(4-tert-butylphenyl)-3-pyridin-3-yl-1H-pyrazol-5-yl]pentanoyl}tyrosinamide;N-{5-[1-(4-tert-butylphenyl)-5-pyridin-3-yl-1H-pyrazol-3-yl]pentanoyl}tyrosinamide;N-{5-[1-(4-tert-butylphenyl)-3-pyridin-4-yl-1H-pyrazol-5-yl]pentanoyl}tyrosinamide;N-{5-[1-(4-tert-butylphenyl)-5-pyridin-4-yl-1H-pyrazol-3-yl]pentanoyl}tyrosinamide;N-{5-[1-(4-tert-butylphenyl)-3-pyridin-3-yl-1H-pyrazol-5-yl]pentanoyl}-N,N-dimethyltyrosinamide;N-(3-[1-(4-tert-butylphenyl)-5-pyridin-3-yl-1H-pyrazol-3-yl]propanoyl)tyrosinamide;N-(3-[1-(4-tert-butylphenyl)-3-pyridin-3-yl-1H-pyrazol-5-yl]propanoyl)tyrosinamideN-[4-(1-butyl-3-isoquinolin-3-yl-1H-pyrazol-5-yl)benzoyl]tyrosinamide;N-{5-[1-(4-isopropylphenyl)-3-pyridin-3-yl-1H-pyrazol-5-yl]pentanoyl}tyrosinamide;N-{6-[1-(4-isopropylphenyl)-3-pyridin-2-yl-1H-pyrazol-5-yl]hexanoyl}tyrosinamide.N-{6-[1-(4-tert-butylphenyl)-3-pyridin-2-yl-1H-pyrazol-5-yl]hexanoyl}-3-hydroxyphenylalaninamide;N-[1-(aminocarbonyl)-3-(4-hydroxyphenyl)propyl]-5-[1-(4-tert-butylphenyl)-3-pyridin-2-yl-1H-pyrazol-5-yl]pentanamide;N-[5-(1-butyl-3-isoquinolin-3-yl-1H-pyrazol-5-yl)pentanoyl]tyrosinamide;N-{6-[1-(4-tert-butylphenyl)-3-pyridin-2-yl-1H-pyrazol-5-yl]hexanoyl}serinamide;N-{6-[1-(4-iso-propylphenyl)-3-pyridin-2-yl-1H-pyrazol-5-yl]hexanoyl}serinamide;N-{6-[1-(4-iso-propylphenyl)-3-pyridin-2-yl-1H-pyrazol-5-yl]hexanoyl}threonamide;N-{5-[1-(4-isopropylphenyl)-3-pyridin-2-yl-1H-pyrazol-5-yl]pentanoyl}tyrosinamide;6-[1-(4-tert-butylphenyl)-3-pyridin-2-yl-1H-pyrazol-5-yl]-N-[2-(4-hydroxyphenyl)ethyl]hexanamide;N-{6-[1-(4-tert-butylphenyl)-3-pyridin-2-yl-1H-pyrazol-5-yl]hexanoyl}tyrosinamide;N-{5-[1-(4-tert-butylphenyl)-3-isoquinolin-3-yl-1H-pyrazol-5-yl]pentanoyl}tyrosinamide;N-{6-[1-(4-tert-butylphenyl)-3-isoquinolin-3-yl-1H-pyrazol-5-yl]hexanoyl}tyrosinamide;N-{6-[1-(4-tert-butylphenyl)-3-pyridin-2-yl-1H-pyrazol-5-yl]hexanoyl}-N-methyltyrosinamide;N-{6-[1-(4-tert-butylphenyl)-3-pyridin-2-yl-1H-pyrazol-5-yl]hexanoyl}-4-(hydroxymethyl)phenylalaninamide;4-amino-N-{6-[1-(4-tert-butylphenyl)-3-pyridin-2-yl-1H-pyrazol-5-yl]hexanoyl}phenylalaninamide;4-(acetylamino)-N-{6-[1-(4-tert-butylphenyl)-3-pyridin-2-yl-1H-pyrazol-5-yl]hexanoyl}phenylalaninamide;4-(aminocarbonyl)-N-{6-[1-(4-tert-butylphenyl)-3-pyridin-2-yl-1H-pyrazol-5-yl]hexanoyl}phenylalaninamide;N-butyl-N-{6-[1-(4-tert-butylphenyl)-3-pyridin-2-yl-1H-pyrazol-5-yl]hexanoyl}tyrosinamide;N-{6-[1-(4-tert-butylphenyl)-3-pyridin-2-yl-1H-pyrazol-5-yl]hexanoyl}threonamide;N-[2-amino-1-(4-hydroxyphenyl)-2-oxoethyl]-6-[1-(4-tert-butylphenyl)-3-pyridin-2-yl-1H-pyrazol-5-yl]hexanamide;N-{2-[4-(aminosulfonyl)phenyl]ethyl}-5-[1-(4-tert-butylphenyl)-3-pyridin-2-yl-1H-pyrazol-5-yl]pentanamide;N-({5-[1-(4-isopropylphenyl)-3-pyridin-2-yl-1H-pyrazol-5-yl]thien-2-yl}carbonyl)tyrosinamide;N-[2-amino-1-(4-hydroxyphenyl)-2-oxoethyl]4-[1-(4-tert-butylphenyl)-3-pyridin-2-yl-1H-pyrazol-5-yl]benzamide;4-[1-(4-tert-butylphenyl)-3-pyridin-2-yl-1H-pyrazol-5-yl]-N-[2-(4-hydroxyphenyl)ethyl]benzamide;N-{3-[1-(4-tert-butylbenzyl)-3-isoquinolin-3-yl-1H-pyrazol-5-yl]benzoyl}tyrosinamide;N-{5-[1-(4-tert-butylphenyl)-3-pyridin-4-yl-1H-pyrazol-5-yl]pentanoyl}tyrosinamide;-N-{3-[1-(4-tert-butylbenzyl)-3-pyridin-3-yl-1H-pyrazol-5-yl]benzoyl}tyrosinamide;N-{3-[1-(4-tert-butylphenyl)-3-isoquinolin-3-yl-1H-pyrazol-5-yl]benzoyl}tyrosinamide;N-[4-(1-butyl-3-isoquinolin-3-yl-1H-pyrazol-5-yl)benzoyl]tyrosinamide;N-{3-[1-(4-tert-butylbenzyl)-3-quinolin-3-yl-1H-pyrazol-5-yl]benzoyl}tyrosinamide;N-{3-[3-isoquinolin-3-yl-1-(4-propylphenyl)-1H-pyrazol-5-yl]benzoyl}tyrosinamide;N-{5-[1-(4-tert-butylphenyl)-3-pyridin-3-yl-1H-pyrazol-5-1]pentanoyl}tyrosinamide;N-{3-[1-(4-tert-butylphenyl)-3-pyridin-3-yl-1H-pyrazol-5-yl]benzoyl}tyrosinamide;N-{4-[1-(4-tert-butylphenyl)-3-pyridin-3-yl-1H-pyrazol-5-yl]benzoyl}tyrosinamide;N-{5-[1-(4-tert-butylbenzyl)-3-pyridin-4-yl-1H-pyrazol-5-yl]pentanoyl}tyrosinamide;N-{3-[1-(4-tert-butylbenzyl)-3-pyridin-4-yl-1H-pyrazol-5-yl]benzoyl}tyrosinamide;N-{5-[1-(4-tert-butylbenzyl)-3-pyridin-3-yl-1H-pyrazol-5-1]pentanoyl}tyrosinamide;N-{5-[1-(4-tert-butylphenyl)-3-pyridin-4-yl-1H-pyrazol-5-yl]pentanoyl}tyrosinamide;N-[3-(1-butyl-3-isoquinolin-3-yl-1H-pyrazol-5-yl)benzoyl]tyrosinamide;N-(4-{[1-(4-tert-butylphenyl)-3-pyridin-4-yl-1H-pyrazol-5-yl]amino}butanoyl)tyrosinamide;N-({3-[1-(4-tert-butylphenyl)-3-pyridin-4-yl-1H-pyrazol-5-yl]propoxy}acetyl)}tyrosinamide;4-[2-({3-[1-(4-tert-butylphenyl)-3-pyridin-4-yl-1H-pyrazol-5-yl]propyl}amino)ethyl]phenol;N-{3-[1-(4-tert-butylphenyl)-3-pyridin-4-yl-1H-pyrazol-5-yl]propyl}tyrosinamide;N-acetyl-N-{3-[1-(4-tert-butylphenyl)-3-pyridin4-yl-1H-pyrazol-5-yl]propyl}tyrosinamide;N-({3-[1-(4-tert-butylphenyl)-3-pyridin-4-yl-1H-pyrazol-5-yl]propoxy}acetyl)tyrosinamide;4-[2-({3-[1-(4-tert-butylphenyl)-3-pyridin-4-yl-1H-pyrazol-5-yl]propyl}amino)ethyl]phenol;N-{3-[1-(4-tert-butylphenyl)-3-pyridin-4-yl-1H-pyrazol-5-yl]propyl}tyrosinamide;N-acetyl-N-{3-[1-(4-tert-butylphenyl)-3-pyridin-4-yl-1H-pyrazol-5-yl]propyl}tyrosinamide;3-[(4-{[1-(4-tert-butylphenyl)-3-pyridin-4-yl-1H-pyrazol-5-yl]amino}butanoyl)amino]4-(4-hydroxyphenyl)butanamide;N-(4-{[1-(4-tert-butylphenyl)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazol-5-yl]amino}butanoyl)tyrosinamide;N-(3-{[1-(4-tert-butylphenyl)-3-pyridin-4-yl-1H-pyrazol-5-yl]amino}propyl)tyrosinamide;N-acetyl-N-(3-{[1-(4-tert-butylphenyl)-3-pyridin-4-yl-1H-pyrazol-5-yl]amino}propyl)tyrosinamide;-N-(4-{[1-(4-tert-butylphenyl)-3-(1-oxidopyridin-4-yl)-1H-pyrazol-5-yl]amino}butanoyl)tyrosinamide;4-{[1-(4-tert-butylphenyl)-3-pyridin-4-yl-1H-pyrazol-5-yl]amino}-N-[2-(4-hydroxyphenyl)ethyl]butanamide;4-{2-[(4-{[1-(4-tert-butylphenyl)-3-pyridin-4-yl-1H-pyrazol-5-yl]amino}butyl)amino]ethyl}phenol;N-(4-{[1-(4-tert-butylphenyl)-3-pyridin-4-yl-1H-pyrazol-5-yl]amino}butanoyl)-N-(2-hydroxyethyl)tyrosinamide;N-(4-{[1-(4-tert-butylphenyl)-3-pyridin-4-yl-1H-pyrazol-5-yl]amino}butanoyl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]tyrosinamide;N-(4-{[1-(4-tert-butylphenyl)-3-pyridin-3-yl-1H-pyrazol-5-yl]amino}butanoyl)tyrosinamide;N-(4-{[1-(4-tert-butylphenyl)-3-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-1H-pyrazol-5-yl]amino}butanoyl)tyrosinamide;(3R)-3-[(4-{[1-(4-tert-butylphenyl)-3-pyridin-3-yl-1H-pyrazol-5-yl]amino}butanoyl)amino]-4-(4-hydroxyphenyl)butanamide;N-(3-{[1-(4-tert-butylphenyl)-3-pyridin-3-yl-1H-pyrazol-5-yl]amino}propyl)tyrosinamide;N-acetyl-N-(3-{[1-(4-tert-butylphenyl)-3-pyridin-3-yl-1H-pyrazol-5-yl]amino}propyl)tyrosinamide;N-(4-{[1-(4-tert-butylphenyl)-3-(1-oxidopyridin-3-yl)-1H-pyrazol-5-yl]amino}butanoyl)tyrosinamide;4-{[1-(4-tert-butylphenyl)-3-pyridin-3-yl-1H-pyrazol-5-yl]amino}-N-[2-(4-hydroxyphenyl)ethyl]butanamide;4-{2-[(4-{[1-(4-tert-butylphenyl)-3-pyridin-3-yl-1H-pyrazol-5-yl]amino}butyl)amino]ethyl}phenol;N-(4-{[1-(4-tert-butylphenyl)-3-pyridin-3-yl-1H-pyrazol-5-yl]amino}butanoyl)-N-(2-hydroxyethyl)tyrosinamide;N-(4-{[1-(4-tert-butylphenyl)-3-pyridin-3-yl-1H-pyrazol-5-yl]amino}butanoyl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]tyrosinamide;N-(4-{[1-(4-tert-butylphenyl)-3-pyridin-3-yl-1H-pyrazol-5-yl]oxy}butanoyl)tyrosinamide;or an optical isomer, racemate or tautomer of any one thereof or apharmaceutically acceptable salt of any one thereof.
 28. A method ofclaims wherein the compound is the following:


29. A method of claims 1 wherein the mammal is a human.
 30. A method ofclaims 1 wherein the mammal is a female.
 31. A method of claims 1wherein the mammal is a male.
 32. A method of claims 1 wherein themammal is a female suffering from an ovulatory disorder.
 33. A method ofclaims 1 wherein the mammal is a female being treated with an assistedreproduction procedure.
 34. A method of claims 1 wherein the mammal is afemale undergoing in-vitro fertilization.
 35. A method of claims 1wherein the mammal is a male suffering from a spermatogenesis disorder.36-56 (cancelled).